Analyte sensors having a signal-to-noise ratio substantially unaffected by non-constant noise

ABSTRACT

Systems and methods of use involving sensors having a signal-to-noise ratio that is substantially unaffected by non-constant noise are provided for continuous analyte measurement in a host. In some embodiments, a continuous analyte measurement system is configured to be wholly, transcutaneously, intravascularly or extracorporeally implanted.

INCORPORATION BY REFERENCE TO RELATED APPLICATIONS

Any and all priority claims identified in the Application Data Sheet, orany correction thereto, are hereby incorporated by reference under 37CFR 1.57. This application is a continuation of U.S. application Ser.No. 16/796,830, filed Feb. 20, 2020, which is a continuation of U.S.application Ser. No. 16/599,072, filed Oct. 10, 2019, now abandoned,which is a continuation of U.S. application Ser. No. 16/453,925, filedJun. 26, 2019, which is a continuation of U.S. application Ser. No.14/145,404, filed Dec. 31, 2013, now U.S. Pat. No. 10,376,143, which isa continuation of Ser. No. 13/732,848, filed Jan. 2, 2013, now U.S. Pat.No. 9,763,609, which is a continuation of U.S. patent application Ser.No. 11/750,907, filed May 18, 2007, now U.S. Pat. No. 8,364,229. Each ofthe aforementioned applications is incorporated by reference herein inits entirety, and each is hereby expressly made a part of thisspecification.

FIELD OF THE INVENTION

The preferred embodiments relate generally to implantable devices, suchas analyte sensors, and methods for detecting and/or measuring ananalyte in a sample, such as a bodily fluid or tissue, as well asdevices and methods for reducing or eliminating noise on a signaldetected by the device.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a disorder in which the pancreas cannot createsufficient insulin (Type I or insulin dependent) and/or in which insulinis not effective (Type 2 or non-insulin dependent). In the diabeticstate, the victim suffers from high blood sugar, which may cause anarray of physiological derangements (for example, kidney failure, skinulcers, or bleeding into the vitreous of the eye) associated with thedeterioration of small blood vessels. A hypoglycemic reaction (low bloodsugar) may be induced by an inadvertent overdose of insulin, or after anormal dose of insulin or glucose-lowering agent accompanied byextraordinary exercise or insufficient food intake.

Conventionally, a diabetic person carries a self-monitoring bloodglucose (SMBG) monitor, which typically comprises uncomfortable fingerpricking methods. Due to the lack of comfort and convenience, a diabeticwill normally only measure his or her glucose level two to four timesper day. Unfortunately, these time intervals are so far spread apartthat the diabetic will likely find out too late, sometimes incurringdangerous side effects, of a hyperglycemic or hypoglycemic condition. Infact, it is not only unlikely that a diabetic will take a timely SMBGvalue, but the diabetic will not know if their blood glucose value isgoing up (higher) or down (lower) based on conventional methods,inhibiting their ability to make educated insulin therapy decisions.

SUMMARY OF THE INVENTION

In a first aspect, an electrochemical analyte sensor for determining aconcentration of an analyte in a host, the sensor configured forinsertion into a host, wherein the sensor comprises at least oneelectrode configured to measure an analyte concentration substantiallycontinuously; and electronics configured to provide a signal measured atthe electrode; wherein the signal comprises an analyte-related componentand a noise component, wherein the noise component comprises asubstantially non-constant non-analyte-related component; and whereinthe sensor is configured such that the substantially non-constantnon-analyte related component does not substantially contribute to thesignal, after sensor break-in, for at least about one day.

In an embodiment of the first aspect, the analyte is glucose.

In an embodiment of the first aspect, the signal contribution due to thenon-constant non-analyte-related component is less than about 20% of thesignal over a time period of at least about one day.

In an embodiment of the first aspect, the signal contribution due to thenon-constant non-analyte-related component is less than about 20% of thesignal over a time period of at least about three days.

In an embodiment of the first aspect, the signal contribution due to thenon-constant non-analyte-related component is less than about 20% of thesignal over a time period of at least about five days.

In an embodiment of the first aspect, the analyte sensor comprises amembrane system disposed over the electrode.

In an embodiment of the first aspect, the membrane system comprisesglucose oxidase.

In an embodiment of the first aspect, the membrane system is configuredto inactivate at least one non-constant noise-causing electroactivespecies formed in a metabolic process of the host.

In an embodiment of the first aspect, the non-constant noise-causingelectroactive species comprises an electroactive species having a redoxpotential that substantially overlaps with a redox potential of ameasured species indicative of the concentration of the analyte.

In an embodiment of the first aspect, the measured species compriseshydrogen peroxide.

In an embodiment of the first aspect, the noise-causing electroactivespecies comprises at least one species selected from the groupconsisting of reactive oxygen species, nitrogen species, and hydrogenperoxide formed in a metabolic process of the host.

In an embodiment of the first aspect, the membrane system is configuredto substantially block passage therethrough of at least one non-constantnoise-causing electroactive species formed in a metabolic process of thehost.

In an embodiment of the first aspect, the membrane system is configuredto consume at least one non-constant noise-causing electroactive speciesformed in a metabolic process of the host.

In an embodiment of the first aspect, at least a portion of the membranesystem comprises a torturous diffusion path configured to renderinactive, at the electrode, at least one non-constant noise-causingelectroactive species formed in a metabolic process of the host.

In an embodiment of the first aspect, the membrane system comprises aHeme compound.

In an embodiment of the first aspect, the membrane system comprises aresistance domain configured to restrict flow of the analytetherethrough.

In an embodiment of the first aspect, the resistance domain comprises apolymer comprising hydrophilic components and hydrophobic components.

In an embodiment of the first aspect, the sensor is configured withelectronics to detect the analyte with a sensitivity of from about 1pA/mg/dl to about 500-pA/mg/dl.

In an embodiment of the first aspect, the signal contribution due to thenon-constant non-analyte-related component is less than about 10% of thesignal over a time period of at least about one day.

In an embodiment of the first aspect, the signal contribution due to thenon-constant non-analyte-related component is less than about 5% of thesignal over a time period of at least about one day.

In an embodiment of the first aspect, the signal contribution due to thenon-constant non-analyte-related component is less than about 1% of thesignal over a time period of at least about one day.

In an embodiment of the first aspect, the electrode comprises adispersed electroactive surface area.

In an embodiment of the first aspect, the dispersed electroactivesurface area comprises a plurality of spaced electroactive surfaceareas.

In an embodiment of the first aspect, the sensor is configured tomeasure the concentration of the analyte along a substantial length ofan in vivo portion of the sensor.

In an embodiment of the first aspect, the sensor comprises an in vivoportion, wherein an area of the electroactive surface covers at leastabout 50% the in vivo portion.

In an embodiment of the first aspect, the electrode comprises anelectroactive surface, wherein the sensor comprises a discontinuousportion, and wherein the electroactive surface is spaced from thediscontinuous portion by a distance substantially farther than adiffusion distance of at least one non-constant noise-causingelectroactive species formed in a metabolic process of the host

In an embodiment of the first aspect, the in vivo portion of the sensoris tapered.

In an embodiment of the first aspect, the analyte-related component ofthe signal is at least about 80% of the signal over a time period of atleast about one day.

In an embodiment of the first aspect, the analyte sensor comprises amembrane system disposed over the electrode and wherein the membranesystem comprises an outer domain comprising a discontinuouslyhydrophilic surface.

In an embodiment of the first aspect, the outer domain comprises atleast about 5 wt. % of a hydrophilic component.

In an embodiment of the first aspect, the hydrophilic componentcomprises polyethylene glycol.

In an embodiment of the first aspect, the outer domain comprises atleast about 10 wt. % of a hydrophilic component.

In an embodiment of the first aspect, the outer domain comprises atleast about 20 wt. % of a hydrophilic component.

In an embodiment of the first aspect, the outer domain is configured tocontrol a flux of the analyte therethrough.

In an embodiment of the first aspect, the analyte sensor is configuredto detect hydrogen peroxide via diffusion to the electrode, wherein thesensor comprises a membrane system disposed over the electrode, whereinthe membrane system comprises an electrode domain adjacent to theelectrode, wherein the electrode domain is configured to maintain alayer of water at electrochemically reactive surfaces of the sensor, andwherein the electrode domain comprises an enzyme configured fordetecting the analyte.

In an embodiment of the first aspect, the analyte sensor is configuredfor ambulatory wear.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph illustrating the components of a signal measured by atranscutaneous glucose sensor (after sensor break-in was complete),implanted in a non-diabetic, human volunteer host.

FIG. 2A is a perspective view of an in vivo portion of an analytesensor, in one embodiment.

FIG. 2B is a perspective view of an in vivo portion of an analytesensor, in one embodiment.

FIG. 2C is a perspective view of an in vivo portion of an analytesensor, in one embodiment.

FIG. 2D is a perspective view of an in vivo portion of an analytesensor, in one embodiment.

FIG. 2E is a cross-sectional view of the analyte sensor of FIG. 2A,taken along line 2E-2E.

FIG. 2F is a cross-sectional view of a membrane system, in oneembodiment.

FIG. 3A is a cross-sectional view of a membrane system, in oneembodiment, illustrating the diffusion distance D₁ between H₂O₂generated within the enzyme domain and the electroactive surface.

FIG. 3B is a cross-sectional view of a membrane system, in anotherembodiment, illustrating the diffusion distance D₂ between H₂O₂generated within the enzyme domain and the electroactive surface.

FIG. 3C is a cross-sectional view of a membrane system, in anotherembodiment, illustrating the diffusion distance D₃ between H₂O₂generated within the enzyme domain and the electroactive surface.

FIG. 4 is a block diagram that illustrates electronics associated with asensor system, in one embodiment.

FIG. 5 is perspective view of a receiver, in one embodiment.

FIG. 6 is a block diagram that illustrates a configuration of a medicaldevice including a continuous analyte sensor, a receiver, and anexternal device, in one embodiment.

FIG. 7 is a flow chart that illustrates the initial calibration and dataoutput of sensor data, in one embodiment.

FIG. 8 is a graph illustrating the signal components of a total signalfrom an analyte sensor, in one embodiment, collected from a volunteerhuman host over a period of 7 days.

FIG. 9 is a graph illustrating the signal components of a total signalfrom an analyte sensor including a lubricious coating, in oneembodiment.

FIG. 10 is a graph illustrating the signal components of a total signalfrom an analyte sensor including a hydrophilic surface treatment, in oneembodiment.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The following description and examples illustrate some exemplaryembodiments of the disclosed invention in detail. Those of skill in theart will recognize that there are numerous variations and modificationsof this invention that are encompassed by its scope. Accordingly, thedescription of a certain exemplary embodiment should not be deemed tolimit the scope of the preferred embodiments.

Definitions

In order to facilitate an understanding of the preferred embodiments, anumber of terms are defined below.

The terms “physiological parameters” and “physiological boundaries” asused herein are broad terms, and are to be given their ordinary andcustomary meaning to a person of ordinary skill in the art (and are notto be limited to a special or customized meaning), and refer withoutlimitation to the parameters obtained from continuous studies ofphysiological data in humans and/or animals. For example, a maximalsustained rate of change of glucose in humans of about 4 to 6 mg/dL/minand a maximum acceleration of the rate of change of about 0.1 to 0.2mg/dL/min² are deemed physiologically feasible limits; values outside ofthese limits would be considered non-physiological. As another example,the rate of change of glucose is lowest at the maxima and minima of thedaily glucose range, which are the areas of greatest risk in patienttreatment, thus a physiologically feasible rate of change can be set atthe maxima and minima based on continuous studies of glucose data. As afurther example, it has been observed that the best solution for theshape of the curve at any point along glucose signal data stream over acertain time period (for example, about 20 to 30 minutes) is a straightline, which can be used to set physiological limits. These terms arebroad enough to include physiological parameters for any analyte.

The term “analyte” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and it is not to be limited to a special or customized meaning),and refers without limitation to a substance or chemical constituent ina biological fluid (for example, blood, interstitial fluid, cerebralspinal fluid, lymph fluid or urine) that can be analyzed. Analytes mayinclude naturally occurring substances, artificial substances,metabolites, and/or reaction products. In some embodiments, the analytefor measurement by the sensor heads, devices, and methods disclosedherein is glucose. However, other analytes are contemplated as well,including but not limited to acarboxyprothrombin; acylcarnitine; adeninephosphoribosyl transferase; adenosine deaminase; albumin;alpha-fetoprotein; amino acid profiles (arginine (Krebs cycle),histidine/urocanic acid, homocysteine, phenylalanine/tyrosine,tryptophan); andrenostenedione; antipyrine; arabinitol enantiomers;arginase; benzoylecgonine (cocaine); biotinidase; biopterin; c-reactiveprotein; carnitine; carnosinase; CD4; ceruloplasmin; chenodeoxycholicacid; chloroquine; cholesterol; cholinesterase; conjugated 1-ßhydroxy-cholic acid; cortisol; creatine kinase; creatine kinase MMisoenzyme; cyclosporin A; d-penicillamine; de-ethylchloroquine;dehydroepiandrosterone sulfate; DNA (acetylator polymorphism, alcoholdehydrogenase, alpha 1-antitrypsin, cystic fibrosis, Duchenne/Beckermuscular dystrophy, analyte-6-phosphate dehydrogenase,hemoglobinopathies A, S, C, and E, D-Punjab, beta-thalassemia, hepatitisB virus, HCMV, HIV-1, HTLV-1, Leber hereditary optic neuropathy, MCAD,RNA, PKU, Plasmodium vivax, sexual differentiation, 21-deoxycortisol);desbutylhalofantrine; dihydropteridine reductase; diptheria/tetanusantitoxin; erythrocyte arginase; erythrocyte protoporphyrin; esterase D;fatty acids/acylglycines; free ß-human chorionic gonadotropin; freeerythrocyte porphyrin; free thyroxine (FT4); free tri-iodothyronine(FT3); fumarylacetoacetase; galactose/gal-1-phosphate;galactose-1-phosphate uridyltransferase; gentamicin; analyte-6-phosphatedehydrogenase; glutathione; glutathione perioxidase; glycocholic acid;glycosylated hemoglobin; halofantrine; hemoglobin variants;hexosaminidase A; human erythrocyte carbonic anhydrase I; 17alpha-hydroxyprogesterone; hypoxanthine phosphoribosyl transferase;immunoreactive trypsin; lactate; lead; lipoproteins ((a), B/A-1, ß);lysozyme; mefloquine; netilmicin; phenobarbitone; phenytoin;phytanic/pristanic acid; progesterone; prolactin; prolidase; purinenucleoside phosphorylase; quinine; reverse tri-iodothyronine (rT3);selenium; serum pancreatic lipase; sissomicin; somatomedin C; specificantibodies (adenovirus, anti-nuclear antibody, anti-zeta antibody,arbovirus, Aujeszky's disease virus, dengue virus, Dracunculusmedinensis, Echinococcus granulosus, Entamoeba histolytica, enterovirus,Giardia duodenalisa, Helicobacter pylori, hepatitis B virus, herpesvirus, HIV-1, IgE (atopic disease), influenza virus, Leishmaniadonovani, leptospira, measles/mumps/rubella, Mycobacterium leprae,Mycoplasma pneumoniae, Myoglobin, Onchocerca volvulus, parainfluenzavirus, Plasmodium falciparum, poliovirus, Pseudomonas aeruginosa,respiratory syncytial virus, rickettsia (scrub typhus), Schistosomamansoni, Toxoplasma gondii, Trepenoma pallidium, Trypanosomacruzi/rangeli, vesicular stomatis virus, Wuchereria bancrofti, yellowfever virus); specific antigens (hepatitis B virus, HIV-1);succinylacetone; sulfadoxine; theophylline; thyrotropin (TSH); thyroxine(T4); thyroxine-binding globulin; trace elements; transferrin;UDP-galactose-4-epimerase; urea; uroporphyrinogen I synthase; vitamin A;white blood cells; and zinc protoporphyrin. Salts, sugar, protein, fat,vitamins, and hormones naturally occurring in blood or interstitialfluids may also constitute analytes in certain embodiments. The analytemay be naturally present in the biological fluid, for example, ametabolic product, a hormone, an antigen, an antibody, and the like.Alternatively, the analyte may be introduced into the body, for example,a contrast agent for imaging, a radioisotope, a chemical agent, afluorocarbon-based synthetic blood, or a drug or pharmaceuticalcomposition, including but not limited to insulin; ethanol; cannabis(marijuana, tetrahydrocannabinol, hashish); inhalants (nitrous oxide,amyl nitrite, butyl nitrite, chlorohydrocarbons, hydrocarbons); cocaine(crack cocaine); stimulants (amphetamines, methamphetamines, Ritalin,Cylert, Preludin, Didrex, PreState, Voranil, Sandrex, Plegine);depressants (barbituates, methaqualone, tranquilizers such as Valium,Librium, Miltown, Serax, Equanil, Tranxene); hallucinogens(phencyclidine, lysergic acid, mescaline, peyote, psilocybin); narcotics(heroin, codeine, morphine, opium, meperidine, Percocet, Percodan,Tussionex, Fentanyl, Darvon, Talwin, Lomotil); designer drugs (analogsof fentanyl, meperidine, amphetamines, methamphetamines, andphencyclidine, for example, Ecstasy); anabolic steroids; and nicotine.The metabolic products of drugs and pharmaceutical compositions are alsocontemplated analytes. Analytes such as neurochemicals and otherchemicals generated within the body may also be analyzed, such as, forexample, ascorbic acid, uric acid, dopamine, noradrenaline,3-methoxytyramine (3MT), 3,4-dihydroxyphenylacetic acid (DOPAC),homovanillic acid (HVA), 5-hydroxytryptamine (5HT), and5-hydroxyindoleacetic acid (FHIAA).

The term “continuous glucose sensor” as used herein is a broad term, andis to be given its ordinary and customary meaning to a person ofordinary skill in the art (and it is not to be limited to a special orcustomized meaning), and refers without limitation to a device thatcontinuously or continually measures glucose concentration, for example,at time intervals ranging from fractions of a second up to, for example,1, 2, or 5 minutes, or longer. It should be understood that continuousglucose sensors can continually measure glucose concentration withoutrequiring user initiation and/or interaction for each measurement, suchas described with reference to U.S. Pat. No. 6,001,067, for example.

The phrase “continuous glucose sensing” as used herein is a broad term,and is to be given its ordinary and customary meaning to a person ofordinary skill in the art (and it is not to be limited to a special orcustomized meaning), and refers without limitation to the period inwhich monitoring of glucose concentration is continuously or continuallyperformed, for example, at time intervals ranging from fractions of asecond up to, for example, 1, 2, or 5 minutes, or longer.

The term “biological sample” as used herein is a broad term, and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to a sample of a host body, forexample, blood, interstitial fluid, spinal fluid, saliva, urine, tears,sweat, tissue, and the like.

The term “host” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and it is not to be limited to a special or customized meaning), andrefers without limitation to plants or animals, for example humans.

The term “biointerface membrane” as used herein is a broad term, and isto be given its ordinary and customary meaning to a person of ordinaryskill in the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to a permeable or semi-permeablemembrane that can include one or more domains and is typicallyconstructed of materials of a few microns thickness or more, which canbe placed over the sensing region to keep host cells (for example,macrophages) from gaining proximity to, and thereby damaging themembrane system or forming a barrier cell layer and interfering with thetransport of glucose across the tissue-device interface.

The term “membrane system” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to a permeable or semi-permeablemembrane that can be comprised of one or more domains and is typicallyconstructed of materials of a few microns thickness or more, which maybe permeable to oxygen and are optionally permeable to glucose. In oneexample, the membrane system comprises an immobilized glucose oxidaseenzyme, which enables an electrochemical reaction to occur to measure aconcentration of glucose.

The term “domain” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and it is not to be limited to a special or customized meaning), andrefers without limitation to regions of a membrane that can be layers,uniform or non-uniform gradients (for example, anisotropic), functionalaspects of a material, or provided as portions of the membrane.

The term “copolymer” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and it is not to be limited to a special or customized meaning),and refers without limitation to polymers having two or more differentrepeat units and includes copolymers, terpolymers, tetrapolymers, andthe like.

The term “sensing region” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to the region of a monitoringdevice responsible for the detection of a particular analyte. In oneembodiment, the sensing region generally comprises a non-conductivebody, at least one electrode, a reference electrode and a optionally acounter electrode passing through and secured within the body forming anelectrochemically reactive surface at one location on the body and anelectronic connection at another location on the body, and a membranesystem affixed to the body and covering the electrochemically reactivesurface. In another embodiment, the sensing region generally comprises anon-conductive body, a working electrode (anode), a reference electrode(optionally can be remote from the sensing region), an insulatordisposed therebetween, and a multi-domain membrane affixed to the bodyand covering the electrochemically reactive surfaces of the working andoptionally reference electrodes.

The term “electrochemically reactive surface” as used herein is a broadterm, and is to be given its ordinary and customary meaning to a personof ordinary skill in the art (and it is not to be limited to a specialor customized meaning), and refers without limitation to the surface ofan electrode where an electrochemical reaction takes place. In oneembodiment, a working electrode measures hydrogen peroxide creating ameasurable electronic current.

The term “electrochemical cell” as used herein is a broad term, and isto be given its ordinary and customary meaning to a person of ordinaryskill in the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to a device in which chemicalenergy is converted to electrical energy. Such a cell typically consistsof two or more electrodes held apart from each other and in contact withan electrolyte solution. Connection of the electrodes to a source ofdirect electric current renders one of them negatively charged and theother positively charged. Positive ions in the electrolyte migrate tothe negative electrode (cathode) and there combine with one or moreelectrons, losing part or all of their charge and becoming new ionshaving lower charge or neutral atoms or molecules; at the same time,negative ions migrate to the positive electrode (anode) and transfer oneor more electrons to it, also becoming new ions or neutral particles.The overall effect of the two processes is the transfer of electronsfrom the negative ions to the positive ions, a chemical reaction.

The term “enzyme” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and it is not to be limited to a special or customized meaning), andrefers without limitation to a protein or protein-based molecule thatspeeds up a chemical reaction occurring in a living thing. Enzymes mayact as catalysts for a single reaction, converting a reactant (alsocalled an analyte herein) into a specific product. In one exemplaryembodiment of a glucose oxidase-based glucose sensor, an enzyme, glucoseoxidase (GOX) is provided to react with glucose (the analyte) and oxygento form hydrogen peroxide.

The term “co-analyte” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and it is not to be limited to a special or customized meaning),and refers without limitation to a molecule required in an enzymaticreaction to react with the analyte and the enzyme to form the specificproduct being measured. In one exemplary embodiment of a glucose sensor,an enzyme, glucose oxidase (GOX) is provided to react with glucose andoxygen (the co-analyte) to form hydrogen peroxide.

The term “constant analyte” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to an analyte that remainsrelatively constant over a time period, for example over an hour to aday as compared to other variable analytes. For example, in a personwith diabetes, oxygen and urea may be relatively constant analytes inparticular tissue compartments relative to glucose, which is known tooscillate from about 40 to about 400 mg/dL during a 24-hour cycle.Although analytes such as oxygen and urea are known to oscillate to alesser degree, for example due to physiological processes in a host,they are substantially constant, relative to glucose, and can bedigitally filtered, for example low pass filtered, to minimize oreliminate any relatively low amplitude oscillations. Constant analytesother than oxygen and urea are also contemplated.

The term “proximal” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and it is not to be limited to a special or customized meaning),and refers without limitation to near to a point of reference such as anorigin or a point of attachment. For example, in some embodiments of amembrane system that covers an electrochemically reactive surface, theelectrolyte domain is located more proximal to the electrochemicallyreactive surface than the resistance domain.

The term “distal” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and it is not to be limited to a special or customized meaning), andrefers without limitation to spaced relatively far from a point ofreference, such as an origin or a point of attachment. For example, insome embodiments of a membrane system that covers an electrochemicallyreactive surface, a resistance domain is located more distal to theelectrochemically reactive surfaces than the electrolyte domain.

The terms “computer” or “computer system” as used herein are broadterms, and are to be given their ordinary and customary meanings to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to amachine that can be programmed to manipulate data.

The term “modem” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and it is not to be limited to a special or customized meaning), andrefers without limitation to an electronic device for converting betweenserial data from a computer and an audio signal suitable fortransmission over a telecommunications connection to another modem.

The terms “processor module” and “microprocessor” as used herein arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and they are not to be limited toa special or customized meaning), and refer without limitation to acomputer system, state machine, processor, or the like designed toperform arithmetic and logic operations using logic circuitry thatresponds to and processes the basic instructions that drive a computer.

The term “ROM” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and it is not to be limited to a special or customized meaning), andrefers without limitation to read-only memory, which is a type of datastorage device manufactured with fixed contents. ROM is broad enough toinclude EEPROM, for example, which is electrically erasable programmableread-only memory (ROM).

The term “RAM” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and it is not to be limited to a special or customized meaning), andrefers without limitation to a data storage device for which the orderof access to different locations does not affect the speed of access.RAM is broad enough to include SRAM, for example, which is static randomaccess memory that retains data bits in its memory as long as power isbeing supplied.

The term “A/D Converter” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to hardware and/or software thatconverts analog electrical signals into corresponding digital signals.

The term “RF transceiver” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to a radio frequency transmitterand/or receiver for transmitting and/or receiving signals.

The terms “raw data stream” and “data stream” as used herein are broadterms, and are to be given their ordinary and customary meaning to aperson of ordinary skill in the art (and they are not to be limited to aspecial or customized meaning), and refer without limitation to ananalog or digital signal directly related to the analyte concentrationmeasured by the analyte sensor. In one example, the raw data stream isdigital data in “counts” converted by an A/D converter from an analogsignal (for example, voltage or amps) representative of an analyteconcentration. The terms broadly encompass a plurality of time spaceddata points from a substantially continuous analyte sensor, whichcomprises individual measurements taken at time intervals ranging fromfractions of a second up to, for example, 1, 2, or 5 minutes or longer.In some embodiments, raw data includes one or more values (e.g., digitalvalue) representative of the current flow integrated over time (e.g.,integrated value), for example, using a charge counting device, or thelike.

The term “counts” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and it is not to be limited to a special or customized meaning), andrefers without limitation to a unit of measurement of a digital signal.In one example, a raw data stream measured in counts is directly relatedto a voltage (for example, converted by an A/D converter), which isdirectly related to current from a working electrode.

The term “electronic circuitry” as used herein is a broad term, and isto be given its ordinary and customary meaning to a person of ordinaryskill in the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to the components (for example,hardware and/or software) of a device configured to process data. In thecase of an analyte sensor, the data includes biological informationobtained by a sensor regarding the concentration of the analyte in abiological fluid. U.S. Pat. Nos. 4,757,022, 5,497,772 and 4,787,398,which are hereby incorporated by reference in their entirety, describesuitable electronic circuits that can be utilized with devices ofcertain embodiments.

The term “potentiostat” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to an electrical system thatapplies a potential between the working and reference electrodes of atwo- or three-electrode cell at a preset value and measures the currentflow through the working electrode. Typically, the potentiostat forceswhatever current is necessary to flow between the working and referenceor counter electrodes to keep the desired potential, as long as theneeded cell voltage and current do not exceed the compliance limits ofthe potentiostat.

The terms “operably connected” and “operably linked” as used herein arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and they are not to be limited toa special or customized meaning), and refer without limitation to one ormore components being linked to another component(s) in a manner thatallows transmission of signals between the components. For example, oneor more electrodes can be used to detect the amount of glucose in asample and convert that information into a signal; the signal can thenbe transmitted to an electronic circuit. In this case, the electrode is“operably linked” to the electronic circuit. These terms are broadenough to include wired and wireless connectivity.

The term “smoothing” and “filtering” as used herein are broad terms, andare to be given their ordinary and customary meaning to a person ofordinary skill in the art (and they are not to be limited to a specialor customized meaning), and refer without limitation to modification ofa set of data to make it smoother and more continuous and remove ordiminish outlying points, for example, by performing a moving average ofthe raw data stream.

The term “algorithm” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and it is not to be limited to a special or customized meaning),and refers without limitation to the computational processes (forexample, programs) involved in transforming information from one stateto another, for example using computer processing.

The term “regression” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and it is not to be limited to a special or customized meaning),and refers without limitation to finding a line in which a set of datahas a minimal measurement (for example, deviation) from that line.Regression can be linear, non-linear, first order, second order, and soforth. One example of regression is least squares regression.

The term “pulsed amperometric detection” as used herein is a broad term,and is to be given its ordinary and customary meaning to a person ofordinary skill in the art (and it is not to be limited to a special orcustomized meaning), and refers without limitation to an electrochemicalflow cell and a controller, which applies the potentials and monitorscurrent generated by the electrochemical reactions. The cell can includeone or multiple working electrodes at different applied potentials.Multiple electrodes can be arranged so that they face thechromatographic flow independently (parallel configuration), orsequentially (series configuration).

The term “calibration” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to the relationship and/or theprocess of determining the relationship between the sensor data andcorresponding reference data, which may be used to convert sensor datainto meaningful values substantially equivalent to the reference. Insome embodiments, namely in continuous analyte sensors, calibration maybe updated or recalibrated over time if changes in the relationshipbetween the sensor and reference data occur, for example due to changesin sensitivity, baseline, transport, metabolism, or the like.

The term “sensor analyte values” and “sensor data” as used herein arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and they are not to be limited toa special or customized meaning), and refer without limitation to datareceived from a continuous analyte sensor, including one or moretime-spaced sensor data points.

The term “reference analyte values” and “reference data” as used hereinare broad terms, and are to be given their ordinary and customarymeaning to a person of ordinary skill in the art (and they are not to belimited to a special or customized meaning), and refer withoutlimitation to data from a reference analyte monitor, such as a bloodglucose meter, or the like, including one or more reference data points.In some embodiments, the reference glucose values are obtained from aself-monitored blood glucose (SMBG) test (for example, from a finger orforearm blood test) or an YSI (Yellow Springs Instruments) test, forexample.

The term “matched data pairs” as used herein is a broad term, and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to reference data (for example,one or more reference analyte data points) matched with substantiallytime corresponding sensor data (for example, one or more sensor datapoints).

The terms “interferants” and “interfering species” as used herein arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to effectsand/or species that interfere with the measurement of an analyte ofinterest in a sensor so as to produce a signal that does not accuratelyrepresent the analyte measurement. In one example of an electrochemicalsensor, interfering species are compounds with an oxidation potentialthat overlaps with that of the analyte to be measured, producing a falsepositive signal. In another example of an electrochemical sensor,interfering species are substantially non-constant compounds (e.g., theconcentration of an interfering species fluctuates over time).Interfering species include but are not limited to compounds withelectroactive acidic, amine or sulfhydryl groups, urea, lactic acid,phosphates, citrates, peroxides, amino acids, amino acid precursors orbreak-down products, nitric oxide (NO), NO-donors, NO-precursors,acetaminophen, ascorbic acid, bilirubin, cholesterol, creatinine,dopamine, ephedrine, ibuprofen, L-dopa, methyl dopa, salicylate,tetracycline, tolazamide, tolbutamide, triglycerides, and uric acidelectroactive species produced during cell metabolism and/or woundhealing, electroactive species that arise during body pH changes and thelike. Electroactive species that cause constant and/or non-constantnoise are included in the definitions of “interferants” and “interferingspecies”.

The term “bifunctional” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to having or serving twofunctions. For example, in a needle-type analyte sensor, a metal wire isbifunctional because it provides structural support and acts as anelectrical conductor.

The term “function” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and it is not to be limited to a special or customized meaning),and refers without limitation to an action or use for which something issuited or designed.

The term “electrical conductor” as used herein is a broad term, and isto be given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning) and refers without limitation to materials that contain movablecharges of electricity. When an electric potential difference isimpressed across separate points on a conductor, the mobile chargeswithin the conductor are forced to move, and an electric current betweenthose points appears in accordance with Ohm's law.

Accordingly, the term “electrical conductance” as used herein is a broadterm, and is to be given its ordinary and customary meaning to a personof ordinary skill in the art (and is not to be limited to a special orcustomized meaning) and refers without limitation to the propensity of amaterial to behave as an electrical conductor. In some embodiments, theterm refers to a sufficient amount of electrical conductance (e.g.,material property) to provide a necessary function (electricalconduction).

The terms “insulative properties,” “electrical insulator” and“insulator” as used herein are broad terms, and are to be given theirordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning) and referswithout limitation to the tendency of materials that lack mobile chargesto prevent movement of electrical charges between two points. In oneexemplary embodiment, an electrically insulative material may be placedbetween two electrically conductive materials, to prevent movement ofelectricity between the two electrically conductive materials. In someembodiments, the terms refer to a sufficient amount of insulativeproperty (e.g., of a material) to provide a necessary function(electrical insulation). The terms “insulator” and “non-conductivematerial” can be used interchangeably herein.

The term “structural support” as used herein is a broad term, and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning) and refers without limitation to the tendency of a material tokeep the sensor's structure stable or in place. For example, structuralsupport can include “weight bearing” as well as the tendency to hold theparts or components of a whole structure together. A variety ofmaterials can provide “structural support” to the sensor.

The term “diffusion barrier” as used herein is a broad term, and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning) and refers without limitation to something that obstructs therandom movement of compounds, species, atoms, molecules, or ions fromone site in a medium to another. In some embodiments, a diffusionbarrier is structural, such as a wall that separates two workingelectrodes and substantially prevents diffusion of a species from oneelectrode to the other. In some embodiments, a diffusion barrier isspatial, such as separating working electrodes by a distancesufficiently large enough to substantially prevent a species at a firstelectrode from affecting a second electrode. In other embodiments, adiffusion barrier can be temporal, such as by turning the first andsecond working electrodes on and off, such that a reaction at a firstelectrode will not substantially affect the function of the secondelectrode.

The terms “integral,” “integrally,” “integrally formed,” integrallyincorporated,” “unitary” and “composite” as used herein are broad terms,and are to be given their ordinary and customary meaning to a person ofordinary skill in the art (and they are not to be limited to a specialor customized meaning), and refer without limitation to the condition ofbeing composed of essential parts or elements that together make awhole. The parts are essential for completeness of the whole. In oneexemplary embodiment, at least a portion (e.g., the in vivo portion) ofthe sensor is formed from at least one platinum wire at least partiallycovered with an insulative coating, which is at least partiallyhelically wound with at least one additional wire, the exposedelectroactive portions of which are covered by a membrane system (seedescription of FIG. 1B or 9B); in this exemplary embodiment, eachelement of the sensor is formed as an integral part of the sensor (e.g.,both functionally and structurally).

The term “coaxial” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and it is not to be limited to a special or customized meaning),and refers without limitation to having a common axis, having coincidentaxes or mounted on concentric shafts.

The term “twisted” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and it is not to be limited to a special or customized meaning),and refers without limitation to united by having one part or end turnedin the opposite direction to the other, such as, but not limited to thetwisted strands of fiber in a string, yarn, or cable.

The term “helix” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and it is not to be limited to a special or customized meaning), andrefers without limitation to a spiral or coil, or something in the formof a spiral or coil (e.g. a corkscrew or a coiled spring). In oneexample, a helix is a mathematical curve that lies on a cylinder or coneand makes a constant angle with the straight lines lying in the cylinderor cone. A “double helix” is a pair of parallel helices intertwinedabout a common axis, such as but not limited to that in the structure ofDNA.

The term “in vivo portion” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to a portion of a device that isto be implanted or inserted into the host. In one exemplary embodiment,an in vivo portion of a transcutaneous sensor is a portion of the sensorthat is inserted through the host's skin and resides within the host.

The term “sensor break-in” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to the time required for thesensor's output signal to provide a substantially linear response to theanalyte concentration (e.g., glucose level). In some embodiments, sensorbreak-in generally includes both electrochemical break-in and membranebreak-in.

The term “membrane break-in” as used herein is a broad term, and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to a time necessary for themembrane to equilibrate to its surrounding environment (e.g.,physiological environment in vivo).

The term “electrochemical break-in” as used herein is a broad term, andis to be given its ordinary and customary meaning to a person ofordinary skill in the art (and is not to be limited to a special orcustomized meaning), and refers without limitation to a time, aftersensor insertion in vitro and/or in vivo, at which the current outputfrom the sensor settles to a stable value following the application ofthe potential to the sensor. Numerous methods of acceleratingelectrochemical break-in can be used, such as, but not limited to,configuring the sensor electronics to aid in decreasing the break-intime of the sensor by applying different voltage settings (for example,starting with a higher voltage setting and then reducing the voltagesetting). Additional methods of accelerating sensor break-in time aredescribed in U.S. Pat. No. 5,411,647, for example, which is incorporatedherein by reference in its entirety.

The “noise” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to a component of an analyte sensor signalthat is not related to the analyte concentration. In one example of aglucose sensor, the noise is composed substantially of signalcontribution due to factors other than glucose (for example, interferingspecies, non-reaction-related hydrogen peroxide, or other electroactivespecies with an oxidation potential that overlaps with hydrogenperoxide). In general, noise comprises components related to constantand non-constant factors (e.g., constant noise and non-constant noise),including endogenous and exogenous interfering species.

The term “constant noise” and “constant background” as used herein arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and it is not to be limited to aspecial or customized meaning), and refer without limitation to thecomponent of the noise signal that remains relatively constant overtime. In some embodiments, constant noise may be referred to as“background” or “baseline.” For example, certain electroactive compoundsfound in the human body are relatively constant factors (e.g., baselineof the host's physiology). In some circumstances, constant backgroundnoise can slowly drift over time (e.g., increase or decrease), howeverthis drift need not adversely affect the accuracy of a sensor, forexample, because a sensor can be calibrated and re-calibrated and/or thedrift measured and compensated for.

The term “non-constant noise” or non-constant background” as used hereinare broad terms, and are to be given their ordinary and customarymeaning to a person of ordinary skill in the art (and it is not to belimited to a special or customized meaning), and refer withoutlimitation to a component of the background signal that is relativelynon-constant, for example, transient and/or intermittent. For example,certain electroactive compounds, are relatively non-constant (e.g.,intermittent interferents due to the host's ingestion, metabolism, woundhealing, and other mechanical, chemical and/or biochemical factors),which create intermittent (e.g., non-constant) “noise” on the sensorsignal that can be difficult to “calibrate out” using a standardcalibration equations (e.g., because the background of the signal doesnot remain constant).

The terms “inactive enzyme” or “inactivated enzyme” as used herein arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and it is not to be limited to aspecial or customized meaning), and refer without limitation to anenzyme (e.g., glucose oxidase, GOx) that has been rendered inactive(e.g., “killed” or “dead”) and has no enzymatic activity. Enzymes can beinactivated using a variety of techniques known in the art, such as butnot limited to heating, freeze-thaw, denaturing in organic solvent,acids or bases, cross-linking, genetically changing enzymaticallycritical amino acids, and the like. In some embodiments, a solutioncontaining active enzyme can be applied to the sensor, and the appliedenzyme subsequently inactivated by heating or treatment with aninactivating solvent.

The term “non-enzymatic” as used herein is a broad term, and is to begiven their ordinary and customary meaning to a person of ordinary skillin the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to a lack of enzyme activity. Insome embodiments, a “non-enzymatic” membrane portion contains no enzyme;while in other embodiments, the “non-enzymatic” membrane portioncontains inactive enzyme. In some embodiments, an enzyme solutioncontaining inactive enzyme or no enzyme is applied.

The term “GOX” as used herein is a broad term, and is to be given theirordinary and customary meaning to a person of ordinary skill in the art(and it is not to be limited to a special or customized meaning), andrefers without limitation to the enzyme Glucose Oxidase (e.g., GOX orGOx is an abbreviation/acronym).

The term “mechanism” as used herein is a broad term, and is to be giventheir ordinary and customary meaning to a person of ordinary skill inthe art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to a process, technique, orsystem for achieving a result. The term is not limited by the processes,techniques or systems described herein, but also includes any process,technique, or system that can achieve a stated result.

The term “redox” as used herein is a broad term, and is to be giventheir ordinary and customary meaning to a person of ordinary skill inthe art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to “oxidation/reduction,” whichdescribes all chemical reactions in which atoms have their oxidationnumber (oxidation state) changed. The term “oxidation” describes theloss of electrons by a molecule, atom or ion. In contrast, the term“reduction” describes the gain of electrons by a molecule, atom or ion.For example, hydrogen peroxide reduces to hydroxide in the presence ofan acid:

H₂O₂+2e ⁻→2 OH⁻

The term “redox potential” as used herein is a broad term, and is to begiven their ordinary and customary meaning to a person of ordinary skillin the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to the tendency of a chemicalspecies to acquire electrons and thereby be reduced. Each species hasits own intrinsic reduction potential, the more positive the potential,the greater the species' affinity for electrons and tendency to bereduced.

The term “hydrophilic” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to the property of havingaffinity for water. For example, a hydrophilic polymer (e.g., having ahydrophilic component) is primarily soluble in water or has a tendencyto absorb water. In general, the more hydrophilic a polymer is, the morethat polymer tends to dissolve in, mix with, or be wetted by water. Inone exemplary embodiment, the hydrophilic component of a hydrophilicpolymer promotes the movement of water (e.g., by diffusion or othermeans) through a membrane formed of the hydrophilic polymer, such as bylowering the thermodynamic barrier to movement of water through themembrane. In some embodiments, a hydrophilic polymer includes ahydrophilic-hydrophobic or hydrophobic-hydrophilic polymer.

The terms “hydrophilic-hydrophobic” and “hydrophobic-hydrophilic” asused herein are broad terms, and are to be given their ordinary andcustomary meaning to a person of ordinary skill in the art (and are notto be limited to a special or customized meaning), and refer withoutlimitation to the property of having both hydrophilic and hydrophobicsubstituents and/or characteristics, such as, for example, a polymer.The terms hydrophilic-hydrophobic and hydrophobic-hydrophilic are usedinterchangeably herein, and are not meant to imply if either thehydrophilic or the hydrophobic substituents are the major component ofthe polymer.

The term “hydrophobic” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to the property of lackingaffinity for, or even repelling, water. For example, the morehydrophobic a polymer, the more that polymer tends to not dissolve in,not mix with, or not be wetted by water. Hydrophilicity andhydrophobicity can be spoken of in relative terms, such as but notlimited to a spectrum of hydrophilicity/hydrophobicity within a group ofcompounds. In some embodiments wherein two or more polymers are beingdiscussed, the term “hydrophobic polymer” can be defined based on thepolymer's relative hydrophobicity when compared to another, morehydrophilic polymer. In some embodiments, a hydrophobic polymer includesa hydrophobic-hydrophilic or a hydrophilic-hydrophobic polymer.

The term “clinical acceptability” as used herein is a broad term, and isto be given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to determination of the risk ofan inaccuracy to a patient. Clinical acceptability considers a deviationbetween time corresponding analyte measurements (for example, data froma glucose sensor and data from a reference glucose monitor) and the risk(for example, to the decision making of a person with diabetes)associated with that deviation based on the analyte value indicated bythe sensor and/or reference data. An example of clinical acceptabilitycan be 85% of a given set of measured analyte values within the “A” and“B” region of a standard Clarke Error Grid when the sensor measurementsare compared to a standard reference measurement.

The term “comprising” as used herein is synonymous with “including,”“containing,” or “characterized by,” and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps.

The terms “substantial” and “substantially” as used herein are broadterms, and are to be given their ordinary and customary meaning to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to asufficient amount that provides a desired function. For example, theinterference domain of some embodiments is configured to resist asufficient amount of interfering species such that tracking of glucoselevels can be achieved, which may include an amount greater than 50percent, an amount greater than 60 percent, an amount greater than 70percent, an amount greater than 80 percent, and an amount greater than90 percent of interfering species. In one exemplary embodiment, twocompounds are “substantially blended;” meaning that the two compoundsare mixed together and at least more than 50% of the molecules of thetwo compounds are not chemically linked (e.g., cross-linked). In a morepreferred exemplary embodiment, at least 70, 75, 80, 85, 90 or 90%, ormore, of the blended compounds are not chemically linked. In anexemplary embodiment of a substantial blend of a silicone polymer and ahydrophilic copolymer, at least 95% or more of the silicone polymer isnot chemically cross-linked with the hydrophilic copolymer. In somepreferred embodiments, the phrase “substantially accurate” means thatthe calibrated analyte level is sufficiently accurate to be displayed tothe host, for example, due to its clinical acceptability or statisticalaccuracy. For example, the data meet the ±20% accuracy standard (e.g.,wherein the data are compared to a gold standard, such as YSI) for bloodglucose meters (BGM) established by the U.S. Food and DrugAdministration (FDA). In some exemplary embodiments, the non-constantnoise component of the total signal is less than 20% of the total signalfor at least one day. In another exemplary embodiment, the analytecomponent of the total signal is greater than 80% of the total signalfor at least one day.

Overview

The preferred embodiments generally relate to implantable devices andmethods of use, for detecting an analyte in a host, including a sensorexhibiting a signal-to-noise ratio that is not substantially affected bynon-constant noise. For example, the signal-to-noise ratio can beattained by incorporating sensor configurations that reduce and/oreliminate the effects of noise-causing interfering species as well assensor configurations that increase the analyte component of the totalsignal detected.

Although the description that follows is primarily directed at glucosemonitoring devices, these sensor configurations are not limited to usein devices that measure or monitor glucose. Rather, these sensorconfigurations can be applied to a variety of devices, including forexample, those that detect and quantify other analytes present inbiological fluids (including, but not limited to, cholesterol, aminoacids and lactate), especially those analytes that are substrates foroxidase enzymes (see, e.g., U.S. Pat. No. 4,703,756), celltransplantation devices (U.S. Pat. Nos. 6,015,572, 5,964,745 and6,083,523), drug delivery devices (U.S. Pat. Nos. 5,458,631, 5,820,589,and 5,972,369) and electrical delivery and/or measuring devices such asimplantable pulse generation cardiac pacing devices (U.S. Pat. Nos.6,157,860, 5,782,880, and 5,207,218), electrocardiogram device (U.S.Pat. Nos. 4,625,730 and 5,987,352) and electrical nerve stimulatingdevices (U.S. Pat. Nos. 6,175,767, 6,055,456, and 4,940,065).

Noise

Generally, implantable sensors measure a signal related to an analyte ofinterest in a host. For example, an electrochemical sensor can measureglucose, creatinine, or urea in a host, such as an animal (e.g., ahuman). Generally, the signal is converted mathematically to a numericvalue indicative of analyte status, such as analyte concentration. Thesignal detected by the sensor can be broken down into its componentparts. For example, in an enzymatic electrochemical analyte sensor,preferably after sensor break-in is complete, the total signal can bedivided into an “analyte component,” which is representative of analyte(e.g., glucose) concentration, and a “noise component,” which is causedby non-analyte-related species that have a redox potential thatsubstantially overlaps with the redox potential of the analyte (ormeasured species, e.g., H₂O₂) at an applied voltage. The noise componentcan be further divided into its component parts, i.e., constant andnon-constant noise. It is not unusual for a sensor to experience acertain level of noise. In general, “constant noise” (sometimes referredto as constant background or baseline) is caused by non-analyte-relatedfactors that are relatively stable over time, including but not limitedto electroactive species that arise from generally constant (e.g.,daily) metabolic processes. Constant noise can vary widely betweenhosts. In contrast, “non-constant noise” (sometimes referred to asnon-constant background) is caused by non-constant, non-analyte-relatedspecies (e.g., non-constant noise-causing electroactive species) thatarise during transient events, such as during host metabolic processes(e.g., wound healing or in response to an illness), or due to ingestionof certain compounds (e.g., certain drugs). In some circumstances, noisecan be caused by a variety of noise-causing electroactive species, whichare discussed in detail elsewhere herein.

FIG. 1 is a graph illustrating the components of a signal measured by atranscutaneous glucose sensor (after sensor break-in was complete), in anon-diabetic volunteer host. The Y-axis indicates the signal amplitude(in counts) detected by the sensor. The term “counts” as used herein isa broad term, and is to be given its ordinary and customary meaning to aperson of ordinary skill in the art (and it is not to be limited to aspecial or customized meaning), and refers without limitation to a unitof measurement of a digital signal. In one example, a raw data streammeasured in counts is directly related to a voltage (for example,converted by an A/D converter), which is directly related to currentfrom a working electrode. The X-axis indicates time.

The total signal collected by the sensor is represented by line 1000,which includes components related to glucose, constant noise, andnon-constant noise, which are described in more detail elsewhere herein.In some embodiments, the total signal is a raw data stream, which caninclude an averaged or integrated the signal, for example, using acharge-counting device.

The non-constant noise component of the total signal is represented byline 1010. The non-constant noise component 1010 of the total signal1000 can be obtained by filtering the total signal 1000 to obtain afiltered signal 1020 using any of a variety of known filteringtechniques, and then subtracting the filtered signal 1020 from the totalsignal 1000. In some embodiments, the total signal can be filtered usinglinear regression analysis of the n (e.g., 10) most recent sampledsensor values. In some embodiments, the total signal can be filteredusing non-linear regression. In some embodiments, the total signal canbe filtered using a trimmed regression, which is a linear regression ofa trimmed mean (e.g., after rejecting wide excursions of any point fromthe regression line). In this embodiment, after the sensor recordsglucose measurements at a predetermined sampling rate (e.g., every 30seconds), the sensor calculates a trimmed mean (e.g., removes highestand lowest measurements from a data set) and then regresses theremaining measurements to estimate the glucose value. In someembodiments, the total signal can be filtered using a non-recursivefilter, such as a finite impulse response (FIR) filter. An FIR filter isa digital signal filter, in which every sample of output is the weightedsum of past and current samples of input, using only some finite numberof past samples. In some embodiments, the total signal can be filteredusing a recursive filter, such as an infinite impulse response (IIR)filter. An IIR filter is a type of digital signal filter, in which everysample of output is the weighted sum of past and current samples ofinput. In some embodiments, the total signal can be filtered using amaximum-average (max-average) filtering algorithm, which smoothes databased on the discovery that the substantial majority of signal artifactsobserved after implantation of glucose sensors in humans, for example,is not distributed evenly above and below the actual blood glucoselevels. It has been observed that many data sets are actuallycharacterized by extended periods in which the noise appears to trenddownwardly from maximum values with occasional high spikes. To overcomethese downward trending signal artifacts, the max-average calculationtracks with the highest sensor values, and discards the bulk of thelower values. Additionally, the max-average method is designed to reducethe contamination of the data with unphysiologically high data from thehigh spikes. The max-average calculation smoothes data at a samplinginterval (e.g., every 30 seconds) for transmission to the receiver at aless frequent transmission interval (e.g., every 5 minutes), to minimizethe effects of low non-physiological data. First, the microprocessorfinds and stores a maximum sensor counts value in a first set of sampleddata points (e.g., 5 consecutive, accepted, thirty-second data points).A frame shift time window finds a maximum sensor counts value for eachset of sampled data (e.g., each 5-point cycle length) and stores eachmaximum value. The microprocessor then computes a rolling average (e.g.,5-point average) of these maxima for each sampling interval (e.g., every30 seconds) and stores these data. Periodically (e.g., every 10^(th)interval), the sensor outputs to the receiver the current maximum of therolling average (e.g., over the last 10 thirty-second intervals as asmoothed value for that time period (e.g., 5 minutes)). In someembodiments, the total signal can be filtered using a “Cone ofPossibility Replacement Method,” which utilizes physiologicalinformation along with glucose signal values in order define a “cone” ofphysiologically feasible glucose signal values within a human.Particularly, physiological information depends upon the physiologicalparameters obtained from continuous studies in the literature as well asour own observations. A first physiological parameter uses a maximalsustained rate of change of glucose in humans (e.g., about 4 to 5mg/dl/min) and a maximum sustained acceleration of that rate of change(e.g., about 0.1 to 0.2 mg/min/min). A second physiological parameteruses the knowledge that rate of change of glucose is lowest at themaxima and minima, which are the areas of greatest risk in patienttreatment. A third physiological parameter uses the fact that the bestsolution for the shape of the curve at any point along the curve over acertain time period (e.g., about 20-25 minutes) is a straight line. Itis noted that the maximum rate of change can be narrowed in someinstances. Therefore, additional physiological data can be used tomodify the limits imposed upon the Cone of Possibility ReplacementMethod for sensor glucose values. For example, the maximum per minuterate change can be lower when the subject is lying down or sleeping; onthe other hand, the maximum per minute rate change can be higher whenthe subject is exercising, for example. In some embodiments, the totalsignal can be filtered using reference changes in electrode potential toestimate glucose sensor data during positive detection of signalartifacts from an electrochemical glucose sensor, the method hereinafterreferred to as reference drift replacement. In this embodiment, theelectrochemical glucose sensor comprises working, counter, and referenceelectrodes. This method exploits the function of the reference electrodeas it drifts to compensate for counter electrode limitations duringoxygen deficits, pH changes, and/or temperature changes. In alternativeimplementations of the reference drift method, a variety of algorithmscan therefore be implemented based on the changes measured in thereference electrode. Linear algorithms, and the like, are suitable forinterpreting the direct relationship between reference electrode driftand the non-glucose rate limiting signal noise such that appropriateconversion to signal noise compensation can be derived. Additionaldescription of signal filtering can be found in U.S. Patent PublicationNo. US-2005-0043598-A1.

The constant noise signal component 1030 can be obtained by calibratingthe sensor signal using reference data, such as one or more bloodglucose values obtained from a hand-held blood glucose meter, from whichthe baseline “b” of a regression can be obtained, representing theconstant noise signal component 1030.

The analyte signal component 1040 can be obtained by subtracting theconstant noise signal component 1030 from the filtered signal 1020.

Noise is clinically important because it can induce error and can reducesensor performance, such as by providing a signal that causes theanalyte concentration to appear higher or lower than the actual analyteconcentration. For example, upward or high noise (e.g., noise thatcauses the signal to increase) can cause the host's glucoseconcentration to appear higher than it truly is, which can lead toimproper treatment decisions. Similarly, downward or low noise (e.g.,noise that causes the signal to decrease) can cause the host's glucoseconcentration to appear lower than it is, which can also lead toimproper treatment decisions. Accordingly, noise reduction is desirable.

Noise can be caused by a variety of factors, ranging from mechanicalfactors to biological factors. For example, it is known that macro- ormicro-motion, ischemia, pH changes, temperature changes, pressure,stress, or even unknown mechanical, electrical, and/or biochemicalsources can cause noise, in some embodiments. Interfering species, whichare known to cause non-constant noise, can be compounds, such as drugsthat have been administered to the host, or intermittently producedproducts of various host metabolic processes. Exemplary interferentsinclude but are not limited to a variety of drugs (e.g., acetaminophen),H₂O₂ from exterior sources (e.g., produced outside the sensor membranesystem), and reactive metabolic species (e.g., reactive oxygen andnitrogen species, some hormones, etc.). Some known interfering speciesfor a glucose sensor include but are not limited to acetaminophen,ascorbic acid, bilirubin, cholesterol, creatinine, dopamine, ephedrine,ibuprofen, L-dopa, methyldopa, salicylate, tetracycline, tolazamide,tolbutamide, triglycerides, and uric acid. In some embodiments, theinterference domain, described elsewhere herein, of the preferredembodiments is less permeable to one or more of the interfering speciesthan to the measured species, e.g., the product of an enzymatic reactionthat is measured at the electroactive surface(s), such as but notlimited to H₂O₂.

In some experiments of implantable glucose sensors, it was observed thatnoise increased when some hosts were intermittently sedentary, such asduring sleep or sitting for extended periods. When the host began movingagain, the noise quickly dissipated. Noise that occurs duringintermittent, sedentary periods (sometimes referred to as intermittentsedentary noise) can occur during relatively inactive periods, such assleeping. Non-constant, non-analyte-related factors can causeintermittent sedentary noise, such as was observed in one exemplarystudy of non-diabetic individuals implanted with enzymatic-type glucosesensors built without enzyme. These sensors (without enzyme) could notreact with or measure glucose and therefore provided a signal due tonon-glucose effects only (e.g., constant and non-constant noise). Duringsedentary periods (e.g., during sleep), extensive, sustained signal wasobserved on the sensors. Then, when the host got up and moved around,the signal rapidly corrected. As a control, in vitro experiments wereconducted to determine if a sensor component might have leached into thearea surrounding the sensor and caused the noise, but none was detected.From these results, it is believed that a host-produced non-analyterelated reactant was diffusing to the electrodes and producing theunexpected non-constant noise signal.

While not wishing to be bound by theory, it is believed that aconcentration increase of noise-causing electroactive species, such aselectroactive metabolites from cellular metabolism and wound healing,can interfere with sensor function and cause noise observed during hostsedentary periods. For example, local lymph pooling, which can occurwhen a part of the body is compressed or when the body is inactive, cancause, in part, this local build up of interferants (e.g., electroactivemetabolites). Similarly, a local accumulation of wound healing metabolicproducts (e.g., at the site of sensor insertion) likely causes noise onthe sensor. Noise-causing electroactive species can include but are notlimited to compounds with electroactive acidic, amine or sulfhydrylgroups, urea, lactic acid, phosphates, citrates, peroxides, amino acids(e.g., L-arginine), amino acid precursors or break-down products, nitricoxide (NO), NO-donors, NO-precursors or other electroactive species ormetabolites produced during cell metabolism and/or wound healing, forexample. For a more complete discussion of noise and its sources, seeU.S. Patent Publication No. US-2007-0027370-A1.

Noise can be recognized and/or analyzed in a variety of ways. Forexample, in some circumstances, non-constant noise changes faster thanthe analyte signal and/or does not follow an expected analyte signalpattern; and lasts for a period of about 10 hours or more, 8 hours, 6hours, 4 hours, 2 hours, 60 minutes, 30 minutes, or 10 minutes or less.In some embodiments, the sensor data stream can be monitored, signalartifacts detected, and data processing performed based at least in parton whether or not a signal artifact has been detected, such as describedin U.S. Patent Publication No. US-2005-0043598-A1. Additional discussionof noise recognition and analysis can also be found in U.S. PatentPublication No. US-2007-0032706-A1.

In some conventional analyte sensors, non-constant noise can be asignificant component of the total signal, such as 30%, 40%, 50%, 60% ormore of the total signal. Additionally, non-constant noise can occur fordurations of minutes or hours, in some circumstances. In somecircumstances, non-constant noise can be equivalent to a glucoseconcentration of about 400-mg/dl or more. Noise can induce error in thesensor reading, which can reduce sensor accuracy and clinically usefuldata. However, a high level of sensor accuracy is critical forsuccessful patient care and desirable clinical outcomes. In preferredembodiments, as described in greater detail herein, the sensor isconfigured to reduce the non-constant noise component of the signal tobelow 20% of the total signal, such that the negative effects of noiseare is substantially reduced and clinically useful data are provided tothe user.

In preferred embodiments, sensor accuracy is provided by adjusting theratio of the analyte signal to the non-constant noise signal (e.g.,signal-to-noise ratio). In some embodiments, an electrochemical analytedetection system is provided, which includes a sensor configured forsubstantially continuous analyte detection, such as in an ambulatoryhost. The sensor includes at least one electrode and electronicsconfigured to provide a signal measured at the electrode; wherein themeasured signal can be broken down (e.g., after sensor break-in) intoits component parts, a substantially analyte-related component, asubstantially constant non-analyte-related component (i.e., constantnoise) and a substantially non-constant non-analyte-related component(i.e., non-constant noise), wherein the sensor is configured such thatthe substantially non-constant non-analyte-related component does notsubstantially contribute to the signal for at least about one day. Insome preferred embodiments, the signal contribution of the non-constantnoise is less than about 20% of the signal (e.g., total signal) over atime period of at least about one day; in some preferred embodiments,the time period is at least about two, three, four, five, six, sevendays or more, including weeks or months, and the signal contribution ofthe non-constant noise is less than about 18%, 16%, 14%, 12%, 10%, 8%,6%, 5%, 4%, 3%, 2%, or 1%. In some preferred embodiments, the sensor isconfigured such that the signal contribution of the analyte-relatedcomponent is at least about 80% of the signal (e.g., total signal) overa time period of at least about one day; in some preferred embodiments,the time period is at least about two, three, four, five, six, sevendays or more, including weeks or months, and the signal contribution ofthe analyte-related component is at least about 82%, 84%, 86%, 88%, 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more.

A signal component's percentage of the total signal can be determinedusing a variety of methods of quantifying an amplitude of signalcomponents and total signal, from each components percent contributioncan be calculated, as is appreciated by one skilled in the art. In someembodiments, the signal component(s) can be quantified by comparing thepeak-to-peak amplitudes of each signal component for a time period,whereby the peak-to-peak amplitudes of each component can be compared tothe peak-to-peak amplitude of the total signal to determine it'spercentage of the total signal, as is appreciated by one skilled in theart. In some embodiments, the signal component(s) can be quantified bydetermining the Root Mean Square (RMS) of the signal component for atime period. In one exemplary of Root Mean Square analysis of signalcomponents, the signal component(s) can be quantified using the formula:

${RMS} = \sqrt{\frac{\Sigma \left( {x_{1}^{2} + x_{2}^{2} + x_{3}^{2} + x_{n}^{2}} \right)}{n}}$

wherein there are a number (n) of data values (x) for a signal (e.g.,analyte component, non-constant noise component, constant noisecomponent, and/or total signal) during a predetermined time period(e.g., about 1 day, about 2 days, about 3 days, etc). Once the signalcomponents and/or total signal are quantified, the signal components canbe compared to the total signal to determine a percentage of each signalcomponent within the total signal.

Analyte Sensor Configurations/Components

The preferred embodiments provide a continuous analyte sensor thatmeasures a concentration of the analyte of interest or a substanceindicative of the concentration or presence of the analyte. In someembodiments, the analyte sensor is an invasive, minimally invasive, ornon-invasive device, for example a subcutaneous, transdermal,intravascular, or extracorporeal device. In some embodiments, theanalyte sensor may analyze a plurality of intermittent biologicalsamples. The analyte sensor may use any method of analyte-measurement,including enzymatic, chemical, physical, electrochemical,spectrophotometric, polarimetric, calorimetric, radiometric, or thelike.

In general, analyte sensors provide at least one working electrode andat least one reference electrode, which are configured to measure asignal associated with a concentration of the analyte in the host, suchas described in more detail below, and as appreciated by one skilled inthe art. The output signal is typically a raw data stream that is usedto provide a useful value of the measured analyte concentration in ahost to the patient or doctor, for example. However, the analyte sensorsof some embodiments comprise at least one additional working electrodeconfigured to measure at least one additional signal, as discussedelsewhere herein. For example, in some embodiments, the additionalsignal is associated with the baseline and/or sensitivity of the analytesensor, thereby enabling monitoring of baseline and/or sensitivitychanges that may occur in a continuous analyte sensor over time.

In general, continuous analyte sensors define a relationship betweensensor-generated measurements (for example, current in pA, nA, ordigital counts after A/D conversion) and a reference measurement (forexample, glucose concentration mg/dL or mmol/L) that are meaningful to auser (for example, patient or doctor). In the case of an implantablediffusion-based glucose oxidase electrochemical glucose sensor, thesensing mechanism generally depends on phenomena that are linear withglucose concentration, for example: (1) diffusion of glucose through amembrane system (for example, biointerface membrane and membrane system)situated between implantation site and/or the electrode surface, (2) anenzymatic reaction within the membrane system, and (3) diffusion of theH₂O₂ to the sensor. Because of this linearity, calibration of the sensorcan be understood by solving an equation:

y=mx+b

where y represents the sensor signal (e.g., counts), x represents theestimated glucose concentration (e.g., mg/dL), m represents the sensorsensitivity to glucose (e.g., counts/mg/dL), and b represents thebaseline signal (e.g., counts). When both sensitivity m and baseline(background) b change over time in vivo, calibration has generallyrequires at least two independent, matched data pairs (x₁, y₁; x₂, y₂)to solve for m and b and thus allow glucose estimation when only thesensor signal, y is available. Matched data pairs can be created bymatching reference data (for example, one or more reference glucose datapoints from a blood glucose meter, or the like) with substantially timecorresponding sensor data (for example, one or more glucose sensor datapoints) to provide one or more matched data pairs, such as described inco-pending U.S. Patent Publication No. US-2005-0027463-A1. In someimplantable glucose sensors, such as described in more detail in U.S.Pat. No. 6,329,161 to Heller et al., which is incorporated herein byreference in its entirety, the sensing layer utilizes immobilizedmediators (e.g., redox compounds) to electrically connect the enzyme tothe working electrode, rather than using a diffusional mediator. In someimplantable glucose sensors, such as described in more detail in U.S.Pat. No. 4,703,756, the system has two oxygen sensors situated in anoxygen-permeable housing, one sensor being unaltered and the othercontacting glucose oxidase allowing for differential measurement ofoxygen content in bodily fluids or tissues indicative of glucose levels.A variety of systems and methods of measuring glucose in a host areknown, all of which may benefit from some of all of the preferredembodiments to provide a sensor having a signal-to-noise ratio that isnot substantially affected by non-constant noise.

Additional description of analyte sensor configurations can be found inco-pending U.S. patent application Ser. No. 11/692,154, filed on Mar.27, 2007 and entitled “DUAL ELECTRODE SYSTEM FOR A CONTINUOUS ANALYTESENSOR”, U.S. Patent Publication No. US-2007-0027385-A1, and U.S. PatentPublication No. US-2005-0143635-A1

Sensor Components Overview

In some embodiments, an analyte sensor includes a sensing mechanism 34with a small structure (e.g., small-structured, micro- or small diametersensor), for example, a needle-type sensor, in at least a portionthereof (see FIG. 2A). As used herein the term “small-structured”preferably refers to an architecture with at least one dimension lessthan about 1 mm. The small structured sensing mechanism can bewire-based, substrate based, or any other architecture. In somealternative embodiments, the term “small-structured” can also refer toslightly larger structures, such as those having their smallestdimension being greater than about 1 mm, however, the architecture(e.g., mass or size) is designed to minimize the foreign body response(FBR) due to size and/or mass. In some embodiments, a biointerfacemembrane (e.g., membrane system or sensing membrane) is formed onto thesensing mechanism 34 as described in more detail below. In somealternative embodiments, the sensor is configured to be wholly implantedin a host, such as in the host abdomen; such is described in U.S. PatentPublication No. US-2006-0020187-A1. In still other embodiments, thesensor is configured to be implanted in a host vessel orextracorporeally, such as is described in U.S. Patent Publication No.US-2007-0027385-A1, co-pending U.S. patent application Ser. No.11/543,396 filed Oct. 4, 2006, co-pending U.S. patent application Ser.No. 11/691,426 Mar. 26, 2007, and co-pending U.S. patent applicationSer. No. 11/675,063 filed on Feb. 14, 2007.

In the illustrated embodiments, the sensor is an enzyme-basedelectrochemical sensor, wherein the working electrode 38 measures thehydrogen peroxide (H₂O₂) produced by the enzyme catalyzed reaction ofglucose being detected and creates a measurable electronic current (forexample, detection of glucose utilizing glucose oxidase produceshydrogen peroxide as a by-product, H₂O₂ reacts with the surface of theworking electrode producing two protons (2H⁺), two electrons (2e⁻) andone molecule of oxygen (O₂) which produces the electronic current beingdetected), such as described in more detail herein and as is appreciatedby one skilled in the art. Preferably, one or more potentiostat(s) isemployed to monitor the electrochemical reaction at the electroactivesurface of the working electrode(s). The potentiostat applies a constantpotential to the working electrode and its associated referenceelectrode to determine the current produced at the working electrode.The current that is produced at the working electrode (and flows throughthe circuitry to the counter electrode) is substantially proportional tothe amount of H₂O₂ that diffuses to the working electrode. The outputsignal is typically a raw data stream that is used to provide a usefulvalue of the measured analyte concentration in a host to the host ordoctor, for example. In some alternative embodiments, the sensingmechanism includes electrodes deposited on a planar substrate, whereinthe thickness of the implantable portion is less than about 1 mm, see,for example U.S. Pat. Nos. 6,175,752 and 5,779,665.

Some alternative analyte sensors that can benefit from the systems andmethods of some embodiments include U.S. Pat. Nos. 5,711,861, 6,642,015,6,654,625, 6,565,509, 6,514,718, 6,465,066, 6,214,185, 5,310,469, and5,683,562, 6,579,690, 6,484,046, 6,512,939, and 6,424,847, for example.These patents are not inclusive of all applicable analyte sensors; ingeneral, it should be understood that the disclosed embodiments areapplicable to a variety of analyte sensor configurations.

FIG. 2A is an expanded view of an exemplary embodiment of a continuousanalyte sensor 34, also referred to as a transcutaneous analyte sensor,or needle-type sensor, particularly illustrating the sensing mechanism.Preferably, the sensing mechanism comprises a small structure as definedherein and is adapted for insertion under the host's skin, and theremaining body of the sensor (e.g., electronics, etc.) can reside exvivo. In the illustrated embodiment, the analyte sensor 34 includes twoelectrodes, i.e., a working electrode 38 and at least one additionalelectrode 30, which may function as a counter and/or referenceelectrode, hereinafter referred to as the reference electrode 30.

In some exemplary embodiments, each electrode is formed from a fine wirewith a diameter of from about 0.001 or less to about 0.010 inches ormore, for example, and is formed from, e.g., a plated insulator, aplated wire, or bulk electrically conductive material. Although theillustrated electrode configuration and associated text describe onepreferred method of forming a transcutaneous sensor, a variety of knowntranscutaneous sensor configurations can be employed with thetranscutaneous analyte sensor system of some embodiments, such as aredescribed in U.S. Pat. No. 6,695,860 to Ward et al., U.S. Pat. No.6,565,509 to Say et al., U.S. Pat. No. 6,248,067 to Causey III et al.,and U.S. Pat. No. 6,514,718 to Heller et al.

In preferred embodiments, the working electrode comprises a wire formedfrom a conductive material, such as platinum, platinum-iridium,palladium, graphite, gold, carbon, conductive polymer, alloys, or thelike. Although the electrodes can by formed by a variety ofmanufacturing techniques (bulk metal processing, deposition of metalonto a substrate, or the like), it can be advantageous to form theelectrodes from plated wire (e.g., platinum on steel wire) or bulk metal(e.g., platinum wire). It is believed that electrodes formed from bulkmetal wire provide superior performance (e.g., in contrast to depositedelectrodes), including increased stability of assay, simplifiedmanufacturability, resistance to contamination (e.g., which can beintroduced in deposition processes), and improved surface reaction(e.g., due to purity of material) without peeling or delamination.

The working electrode 38 is configured to measure the concentration ofan analyte, such as but not limited to glucose, uric acid, cholesterol,lactate and the like. In an enzymatic electrochemical sensor fordetecting glucose, for example, the working electrode measures thehydrogen peroxide produced by an enzyme catalyzed reaction of theanalyte being detected and creates a measurable electronic current. Forexample, in the detection of glucose wherein glucose oxidase (GOX)produces hydrogen peroxide as a byproduct, H₂O₂ reacts with the surfaceof the working electrode producing two protons (2H⁺), two electrons(2e⁻) and one molecule of oxygen (O₂), which produces the electroniccurrent being detected.

The working electrode 38 is covered with an insulating material, forexample, a non-conductive polymer. Dip-coating, spray-coating,vapor-deposition, or other coating or deposition techniques can be usedto deposit the insulating material on the working electrode. In oneembodiment, the insulating material comprises parylene, which can be anadvantageous polymer coating for its strength, lubricity, and electricalinsulation properties. Generally, parylene is produced by vapordeposition and polymerization of para-xylylene (or its substitutedderivatives). However, any suitable insulating material can be used, forexample, fluorinated polymers, polyethyleneterephthalate, polyurethane,polyimide, other nonconducting polymers, or the like. Glass or ceramicmaterials can also be employed. Other materials suitable for use includesurface energy modified coating systems such as are marketed under thetrade names AMC18, AMC148, AMC141, and AMC321 by Advanced MaterialsComponents Express of Bellafonte, Pa. In some alternative embodiments,however, the working electrode may not require a coating of insulator.

Preferably, the reference electrode 30, which may function as areference electrode alone, or as a dual reference and counter electrode,is formed from silver, silver/silver chloride and the like. Preferably,the electrodes are juxtapositioned and/or twisted with or around eachother; however other configurations are also possible. In one example,the reference electrode 30 is helically wound around the workingelectrode 38 as illustrated in FIG. 2A. The assembly of wires may thenbe optionally coated together with an insulating material, similar tothat described above, in order to provide an insulating attachment(e.g., securing together of the working and reference electrodes).

As described above, conventional transcutaneous devices are believed tosuffer from motion artifacts associated with host movement when the hostis using the device. For example, when a transcutaneous analyte sensoris inserted into the host, various movements on the sensor (for example,relative movement within and between the subcutaneous space, dermis,skin, and external portions of the sensor) create stresses on thedevice, which is known to produce artifacts on the sensor signal (e.g.,non-constant noise). Accordingly, there are different designconsiderations (for example, stress considerations) on various sectionsof the sensor. For example, the in vivo portion of the sensor (e.g., theportion inserted through the host's skin and into the underlying tissue)can benefit in general from greater flexibility as it encounters greatermechanical stresses caused by movement of the tissue within the patientand relative movement between the in vivo and ex vivo portions of thesensor. On the other hand, the ex vivo portion of the sensor (theportion of the sensor that stays outside the body of the host) canbenefit in general from a stiffer, more robust design to ensurestructural integrity and/or reliable electrical connections.Additionally, in some embodiments wherein a needle is retracted over theex vivo portion of the device, a stiffer design can minimize crimping ofthe sensor and/or ease in retraction of the needle from the sensor.Thus, by designing greater flexibility into the in vivo portion, theflexibility is believed to compensate for patient movement, and noiseassociated therewith. By designing greater stiffness into the ex vivoportion, column strength (for retraction of the needle over the sensor),electrical connections, and integrity can be enhanced. In somealternative embodiments, a stiffer distal end and/or a more flexibleproximal end can be advantageous as described in U.S. Patent PublicationNo. US-2006-0015024-A1 and U.S. Patent Publication No.US-2006-0020187-A1.

Some preferred embodiments provide an in vivo portion of the sensor thatis designed to be more flexible than an ex vivo portion of the sensor.The variable stiffness of the sensors of preferred embodiments can beprovided by variable pitch of any one or more helically wound wires ofthe device, variable cross-section of any one or more wires of thedevice, and/or variable hardening and/or softening of any one or morewires of the device, such as is described in more detail with referenceto U.S. Patent Publication No. US-2006-0015024-A1 and U.S. PatentPublication No. US-2006-0020187-A1.

In embodiments wherein an outer insulator is disposed, a portion of thecoated assembly structure can be stripped or otherwise removed, forexample, by hand, excimer lasing, chemical etching, laser ablation,grit-blasting (e.g., with sodium bicarbonate or other suitable grit), orthe like, to expose the electroactive surfaces. Alternatively, a portionof the electrode can be masked prior to depositing the insulator inorder to maintain an exposed electroactive surface area. In oneexemplary embodiment, grit blasting is implemented to expose theelectroactive surfaces, preferably utilizing a grit material that issufficiently hard to ablate the polymer material, while beingsufficiently soft so as to minimize or avoid damage to the underlyingmetal electrode (e.g., a platinum electrode). Although a variety of“grit” materials can be used (e.g., sand, talc, walnut shell, groundplastic, sea salt, and the like), in some preferred embodiments, sodiumbicarbonate is an advantageous grit-material because it is sufficientlyhard to ablate, e.g., a parylene coating without damaging, e.g., anunderlying platinum conductor. One additional advantage of sodiumbicarbonate blasting includes its polishing action on the metal as itstrips the polymer layer, thereby eliminating a cleaning step that mightotherwise be necessary.

In some embodiments, a radial window is formed through the insulatingmaterial to expose a circumferential electroactive surface of theworking electrode. Additionally, sections of electroactive surface ofthe reference electrode are exposed. For example, the sections ofelectroactive surface can be masked during deposition of an outerinsulating layer or etched after deposition of an outer insulatinglayer. In some applications, cellular attack or migration of cells tothe sensor can cause reduced sensitivity and/or function of the device,particularly after the first day of implantation. However, when theexposed electroactive surface is distributed circumferentially about thesensor (e.g., as in a radial window), the available surface area forreaction can be sufficiently distributed so as to minimize the effect oflocal cellular invasion of the sensor on the sensor signal.Alternatively, a tangential exposed electroactive window can be formed,for example, by stripping only one side of the coated assemblystructure. In other alternative embodiments, the window can be providedat the tip of the coated assembly structure such that the electroactivesurfaces are exposed at the tip of the sensor. Other methods andconfigurations for exposing electroactive surfaces can also be employed.

Generally, the sensor electrode(s) can be configured to yield a sensorhaving a signal-to-noise ratio that is not substantially affected bynon-constant noise, such as by systems and methods configured toincrease the analyte signal component and/or decrease the non-constantnoise component.

In some circumstances, noise can be caused (e.g., during use of anamperometric GOX sensor having a platinum-working electrode) byaccumulation of molecular oxygen (O₂) on the platinum electrode, whichis produced during the electro-oxidation of H₂O₂ to water and O₂.Platinum black applied to the working electrode can prevent O₂accumulation on a platinum-working electrode, which prevents theoccurrence of noise on the sensor. Platinum black is a fine black powderof metallic platinum that can be formed into a paste, ink or paint-likematerial, which can be applied to a surface (e.g., wire, plasticsupport) to produce a rough, large surface area coating that isrelatively nonpolarizable. Platinum black can be applied to an electrodesurface using a platinization process (e.g., to a platinum wire or otherplatinum surface) or known thin-film techniques, such as dipping,painting or screen-printing, for example. One additional advantage ofusing platinum black is that a platinum black-coated platinum electrodeaffords substantive signals from hydrogen peroxide oxidation at aworking potential as low as 150 mV, whereas a non-platinum black coatedplatinum electrode must be operated at a potential of at least 600 mV.Since fewer interferents can be electro-oxidized/reduced at the lowerworking potential, non-constant noise on the signal will be reduced insensors operated at a potential lower than 600 mV. Accordingly, in oneembodiment, at least the working electrode is coated with platinumblack, whereby the non-constant noise component of the signal is reducedand the signal-to-noise ratio is thus adjusted (e.g., increased).

In some embodiments, the signal-to-noise ratio can be renderedsubstantially unaffected by non-constant noise by distributing theelectroactive surface area along a substantial length of the in vivoportion of the sensor. In some embodiments, the electroactive surfacearea is distributed along 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, or more of the in vivo portion of the sensor. It is believed thatcertain interfering electroactive species impinge upon the sensor in ascattered manner (e.g., along the length of the in vivo portion of thesensor). In other words, some transient interferents do not necessarilycontact the sensor evenly along the in vivo portion of the sensor. Forexample, the tissue surrounding an implanted sensor is highly variable.In some circumstances, the electroactive surface may be disposed (whenthe sensor is implanted) adjacent to a lymph vessel, which can reducethe local concentration of electroactive species that can interfere withthe analyte signal and result in a minimal non-constant noise componentof the signal. In other circumstances, the electroactive surface may bedisposed (when the sensor is implanted) in fat with poor circulation,which may result in build up of electroactive species that can interferewith the sensor's signal adjacent to the electroactive surface,resulting in more non-constant noise on the sensor's signal (e.g., thanthe surface adjacent to a lymph vessel).

FIG. 2B is a perspective view of an in vivo portion of an analytesensor, in one embodiment, in which the area of electroactive surfacehas been divided into four equal parts (38 a, 38 b, 38 c, 38 d) anddistributed along a substantial length of the in vivo portion of thesensor (e.g., spaced apart from each other by a distance such as 1-mm,2-mm, etc). Accordingly, in some embodiments, the sensor is configuredsuch that the area of the electroactive surface is distributed (e.g.,extending, spaced, divided and/or dispersed) along a substantial lengthof an in vivo portion of the sensor, such that the signal is measured(and can be integrated or averaged) over a more dispersed or distributedportion of the in vivo portion of the sensor (relative to the sensor ofFIG. 2A, for example) such that the signal contribution due to thenon-constant non-analyte component is less than about 20% of the totalsignal (e.g., after sensor break-in has been completed). In someembodiments, the area of the electroactive surface can be distributed ina variety of ways, such as but not limited to two or more areas (e.g.,38 a, 38 b, 38 c, 38 d, etc.), which cumulatively substantially equalthe desired total area of the electroactive surface. The exposed area(s)of the electroactive surface can have any geometric shape, such ascircles, dots, rectangles, ovals, stars, and the like. In someembodiments, the exposed surface areas function essentially asmicroelectrodes along an in vivo portion of the sensor. Microelectrodescan enhance sensor sensitivity, for example by increasing theutilization of the measured electroactive compound due to beneficialedge effects related to a plurality of small surface areas in closeproximity to each other. In one exemplary embodiment, a plurality ofsmall spaced electroactive surface areas are able to detect more H₂O₂generated by a glucose oxidase enzyme layer when the plurality ofelectroactive surfaces are spaced (from each other) within the diffusiondistance of H₂O₂ (e.g., as compared to one or more electroactive surfaceareas spaced more than the diffusion distance of H₂O₂). Although awire-type, small-structured sensor is exemplified in the illustratedembodiment, the surface area of a variety of other analyte sensorconfigurations (e.g., wholly implantable, intravascular, planar-typesensor configured, including implantable continuous sensors and in vitrotest strips) can be distributed as described herein. Methods forexposing the sensor's electroactive surface are detailed in U.S. PatentPublication No. US-2006-0020187-A1.

FIG. 2C is a perspective view of the in vivo portion of an analytesensor in one embodiment, wherein the area of the electroactive surfaceis distributed along a substantial length of the in vivo portion of theanalyte sensor. In this embodiment, the area of the electroactivesurface 38 is distributed by selecting a working electrode with apreferred width, such that the exposed electroactive surface covers asubstantial length of the in vivo portion of the working electrode,while requiring a relatively low current draw. For example, theelectroactive surface can be distributed by using a longer, thinnerarea, such that the electroactive surface covers a substantial length ofthe in vivo portion of the working electrode, but the total exposedsurface area remains unchanged as compared another sensor with a wider,shorter exposed electroactive surface area. For example, in someembodiments, the electrode is formed from a bulk metal wire having adiameter of from about 0.001 to about 0.010 inches. For example, if twosensors are compared, the first sensor having working electrode formedof a 0.001 inch diameter wire with a 1-mm long electroactive surface andthe second sensor having a working electrode formed of a 0.010 inchdiameter wire with a 0.1-mm long electroactive surface, the two sensorscould have the same sensitivity but the signal-to-noise ratio would berendered substantially unaffected by non-constant noise as compare tothat of the second sensor. In some embodiments, the preferred surfacearea of the working electrode is from about 0.0000839-cm² or less toabout 0.016129-cm² or more, assuming a diameter of from about 0.001inches to about 0.010 inches and a length of from about 0.004 inches toabout 0.078 inches.

Referring now to FIGS. 2A-2D, some examples of discontinuous surfaces onthe sensor are shown, including relatively sharp, abrupt edges,substantially raised surface features or substantial and/or abruptchanges in sensor diameter, such as at the sensor tip 31 a and the invivo termination of the reference electrode 31 b. In some circumstances,pockets of a localized, heightened inflammatory response (e.g., anaccumulation of inflammatory cells) can form around portions of thesensor having discontinuous surfaces, such as the sensor tip 31 a andthe in vivo termination 31 b of the reference electrode. This phenomenonhas been observed, in histological sections of rat tissue explants(after one-day of small-structured sensor implantation), as anaccumulation of inflammatory cells around both the sensor tip 31 a andthe in vivo termination 31 b of the reference electrode. In someembodiments, slight diameter changes, such as at the edge of theelectroactive surface area of the working electrode, are designed toavoid or minimize a heightened inflammatory response as described above.Such heightened inflammatory responses can be caused by the presence ofan increased population of macrophages, lymphocytes, neutrophils, and/orforeign body giant cells, which incites the production of highlydiffusible, electroactive noise-causing species in the body, especiallyfree radicals (e.g., reactive oxygen and nitrogen species). Some of thenoise-causing compounds produced by the heightened inflammatory responsecan react at the sensor's working electrode, resulting in noise (e.g.,non-constant noise). Accordingly, it is believed that separating theelectroactive surface of the working electrode from a discontinuoussurface(s), by a distance that is sufficient to minimize or avoid theinfluence of inflammation at the discontinuous surface (e.g., by adistance substantially farther than the diffusion distance of at leastone non-constant noise-causing electroactive species produced by theinflammation), can reduce non-constant noise on the signal to less thanabout 20% of the total signal. In some preferred embodiments, theelectroactive surface of the working electrode is spaced from about0.020, 0.03, 0.04, or 0.05 inches or less to about 0.06, 0.07, 0.08,0.09, or 0.100 inches or more from a discontinuous surface, such thatnon-constant noise is less than about 20% of the total signal and/or theanalyte component is at least 80% of the total signal. For example, inone exemplary embodiment, the sensor is configured such that thereference electrode 30 is spaced from the radial window of the workingelectrode 38 such that the distance (referred to here at the “firstdistance”) between the radial window (e.g., the edge closest to thereference electrode) and the in vivo termination 31 b of the referenceelectrode is at least about 0.020-inches, such that the non-constantnoise component is less than 20% of the total signal and/or the analytecomponent is at least 80% of the total signal. In some exemplaryembodiments, the first distance is at least 0.030, 0.04, 0.050, 0.060,0.070, 0.080, 0.090 or 0.100-inches or more. In some exemplaryembodiments, the sensor is configured such that the distance between thesensor's tip 31 a and the nearest edge of the radial window (referred tohere as the “second distance”) is at least 0.020-inches, such that thenon-constant noise component is less than 20% of the total signal and/orthe analyte component is at least 80% of the total signal. In someexemplary embodiments, the second distance is at least 0.030, 0.04,0.050, 0.060, 0.070, 0.080, 0.090 or 0.100-inches or more. In somecircumstances, a preferred distance between the electroactive surface ofthe working electrode and a discontinuous surface to minimize or avoid aheightened inflammatory response can vary, for example, due to factorssuch as the types/sizes/characteristics of materials used to form thesensor (e.g., electrode material, membrane system components, etc.),differences in tissues into which the sensor is implanted (e.g., type offat, lean or fat, etc.), the physical state of the host (e.g., illnessor injury), the condition of the wound produced during sensorimplantation and the like.

FIG. 2D is a perspective view of an in vivo portion of an analyte sensorin one embodiment. In preferred embodiments, the sensor is configured tominimize discontinuous portions and thereby reduce non-constant noise onthe signal caused by electroactive species produced from the body'sinflammatory response to such discontinuous portions of the sensor. Forexample, in the embodiment shown in FIG. 2D, the sensor is configured tobe substantially non-discontinuous (or substantially continuous) tominimize the inflammatory response, and thus minimize or prevent noiseon the signal, such that non-constant noise is less than 20% of thetotal signal. In one exemplary embodiment, such as shown in FIG. 2D, thetip 31 a of the sensor is tapered 31 c. In another exemplary embodiment,a discontinuity at the in vivo termination of the reference electrode 31b is reduced (e.g., by minimizing the step difference between at the invivo termination of the reference electrode), such that the inflammatoryresponse is substantially avoided and non-constant noise is less thanabout 20% of the total signal and/or the analyte component is at leastabout 80% of the total signal.

In some embodiments, the sensor is configured to substantially reducethe effect of noise-causing electroactive species caused by inflammationand/or the FBR in response to discontinuous portions of the sensor. Insome embodiments, an in vivo portion of the sensor is configured suchthat the electroactive surface 38 is farther away from the sensor tip 31a and/or the end of reference electrode 31 b than the diffusion distanceof at least one noise-causing electroactive species resulting from thehost's metabolic processes (e.g., H₂O₂ produced outside of the sensor).In some embodiments, some or all discontinuous portions of a sensor aresmoothed and/or tapered sufficiently that inflammation and/or a FBR issubstantially minimized, such that that noise-causing compounds producedby the inflammation and/or FBR associated with the discontinuous portiondo not substantially contribute to the signal. Accordingly, in preferredembodiments, the in vivo portion of the sensor is configured to enable asignal, wherein the non-constant noise component of the total signal isless than about 20%.

In the above-exemplified sensor, an overall diameter of not more thanabout 0.030 inches is preferred, more preferably not more than about0.020 inches, and even more preferably not more than about 0.016 inches.In some embodiments, the exposed electroactive surface area has a widthof from about 0.001 inches or less to about 0.010 inches or more,preferably from about 0.002 inches to about 0.008 inches, and morepreferably from about 0.004 inches to about 0.005 inches. The length ofthe window can be from about 0.1 mm (about 0.004 inches) or less toabout 2 mm (about 0.078 inches) or more, and preferably from about 0.5mm (about 0.02 inches) to about 0.75 mm (0.03 inches). In suchembodiments, the exposed surface area of the working electrode ispreferably from about 0.000013 in² (0.0000839 cm²) or less to about0.0025 in² (0.016129 cm²) or more (assuming a diameter of from about0.001 inches to about 0.010 inches and a length of from about 0.004inches to about 0.078 inches). In some embodiments, the exposed surfacearea of the working electrode is selected to produce an analyte signalwith a current in the picoAmp range, such as is described in more detailelsewhere herein. However, a current in the picoAmp range can bedependent upon a variety of factors, for example the electroniccircuitry design (e.g., sample rate, current draw, A/D converter bitresolution, etc.), the membrane system (e.g., permeability of theanalyte through the membrane system), and the exposed surface area ofthe working electrode. Accordingly, the exposed electroactive workingelectrode surface area can be selected to have a value greater than orless than the above-described ranges taking into considerationalterations in the membrane system and/or electronic circuitry. Inpreferred embodiments of a glucose sensor, it can be advantageous tominimize the surface area of the working electrode while maximizing thediffusivity of glucose in order to render the signal-to-noise ratiosubstantially unaffected by non-constant noise while maintaining sensorperformance in both high and low glucose concentration ranges.

In some alternative embodiments, the exposed surface area of the working(and/or other) electrode can be increased by altering the cross-sectionof the electrode itself. For example, in some embodiments thecross-section of the working electrode can be defined by a cross, star,cloverleaf, ribbed, dimpled, ridged, irregular, or other non-circularconfiguration; thus, for any predetermined length of electrode, aspecific increased surface area can be achieved (as compared to the areaachieved by a circular cross-section). Increasing the surface area ofthe working electrode can be advantageous in providing an increasedsignal responsive to the analyte concentration, which in turn can behelpful in improving the signal-to-noise ratio, for example.

In some alternative embodiments, additional electrodes can be includedwithin the assembly, for example, a three-electrode system (working,reference, and counter electrodes) and/or an additional workingelectrode (e.g., an electrode which can be used to generate oxygen,which is configured as a baseline subtracting electrode, or which isconfigured for measuring additional analytes). U.S. Pat. No. 7,081,195,U.S. Patent Publication No. US-2005-0143635-A1, and U.S. PatentPublication No. US-2007-0027385-A1, each of which are incorporated byreference herein, describe some systems and methods for implementing andusing additional working, counter, and/or reference electrodes. In oneimplementation wherein the sensor comprises two working electrodes, thetwo working electrodes are juxtapositioned (e.g., extend parallel toeach other), around which the reference electrode is disposed (e.g.,helically wound). In some embodiments wherein two or more workingelectrodes are provided, the working electrodes can be formed in adouble-, triple-, quad-, etc. helix configuration along the length ofthe sensor (for example, surrounding a reference electrode, insulatedrod, or other support structure). The resulting electrode system can beconfigured with an appropriate membrane system, wherein the firstworking electrode is configured to measure a first signal comprisingglucose and baseline and the additional working electrode is configuredto measure a baseline signal consisting of baseline only (e.g.,configured to be substantially similar to the first working electrodewithout an enzyme disposed thereon). In this way, the baseline signalcan be subtracted from the first signal to produce a glucose-only signalthat is substantially not subject to fluctuations in the baseline and/orinterfering species on the signal. Accordingly, the above-describeddimensions can be altered as desired.

In some embodiments, the sensing region may include reference and/orother electrodes associated with the glucose-measuring working electrodeand/or separate reference and/or counter electrodes associated withoptional auxiliary working electrode(s). In yet another embodiment, thesensing region may include a glucose-measuring working electrode, anauxiliary working electrode, two counter electrodes (one for eachworking electrode), and one shared reference electrode. In yet anotherembodiment, the sensing region may include a glucose-measuring workingelectrode, an auxiliary working electrode, two reference electrodes, andone shared counter electrode. However, a variety of electrode materialsand configurations can be used with the implantable analyte sensor ofthe preferred embodiments.

Co-pending U.S. patent application Ser. No. 11/543,396 filed Oct. 4,2006 and U.S. Patent Publication No. US-2005-0245799-A1 describeadditional configurations for use in different bodily locations. In oneexemplary embodiment, the sensor is configured for transcutaneousimplantation in the host. In another exemplary embodiment, the sensor isconfigured for insertion into the circulatory system, such as aperipheral vein or artery. However, in other embodiments, the sensor isconfigured for insertion into the central circulatory system, such asbut not limited to the vena cava. In still other embodiments, the sensorcan be configured for insertion into an extracorporeal circulationsystem, such as but not limited to a shunt (e.g., from an artery to avein), an extracorporeal blood chemistry analysis device, a dialysismachine or a heart-lung machine (e.g., pumps the blood during heartsurgery). In still another embodiment, the sensor can be configured tobe wholly implantable, as is described in U.S. Pat. No. 6,001,067.

Although some embodiments illustrate one electrode configurationincluding one bulk metal wire helically wound around another bulk metalwire, other electrode configurations are also contemplated. In analternative embodiment, the working electrode comprises a tube with areference electrode disposed or coiled inside, including an insulatortherebetween. Alternatively, the reference electrode comprises a tubewith a working electrode disposed or coiled inside, including aninsulator therebetween. In another alternative embodiment, a polymer(e.g., insulating) rod is provided, wherein the electrodes are deposited(e.g., electro-plated) thereon. In yet another alternative embodiment, ametallic (e.g., steel) rod is provided, coated with an insulatingmaterial, onto which the working and reference electrodes are deposited.In yet another alternative embodiment, one or more working electrodesare helically wound around a reference electrode.

FIG. 2E is a cross-sectional view through the sensor of FIG. 2A on line2E-2E, illustrating the membrane system 32 in one embodiment. In thisembodiment, the membrane system includes an electrode domain 43, aninterference domain 44, and enzyme domain 46, and a diffusion resistancedomain 48 wrapped around the platinum wire working electrode 38. In someembodiments, this membrane system also includes a cell impermeabledomain as described elsewhere herein. In some embodiments, a unitaryresistance domain and cell impermeable domain is included in themembrane system (denoted as the resistance domain 48 in thisillustration). In some embodiments, the transcutaneous wire sensor isconfigured for short-term implantation (e.g., from about 1 to 30 days).

FIG. 2F is an illustration of a cross-section of a membrane system 32 inan alternative embodiment. The membrane system 32 can be used with aglucose sensor such as those described herein. In this embodiment, themembrane system 32 includes an electrode domain 43 most proximal to theelectrochemically reactive surfaces of the working electrode; an(optional) interference domain 44 less proximal to the electrochemicallyreactive surfaces of the working electrode than the electrode domain; anenzyme domain 46 less proximal to the electrochemically reactivesurfaces of the working electrode than the interference domain; adiffusion resistance domain 48 less proximal to the electrochemicallyreactive surfaces of the working electrode than the enzyme domain; acell impermeable domain 42 (also referred to as a bioprotective layer)less proximal to the electrochemically reactive surfaces of the workingelectrode than the diffusion resistance domain; and an optional celldisruptive domain 40 most distal of all domains from theelectrochemically reactive surfaces of the working electrode. However,it is understood that the membrane system 32 can be modified for use inother devices, by including only two or more of the layers, oradditional layers not recited above.

In general, the sensing membranes 32 of some embodiments include aplurality of domains or layers, for example, an interference domain 44,an enzyme domain 46, and a resistance domain 48, and may includeadditional domains, such as an electrode domain 43, a cell impermeabledomain 42 (also referred to as a bioprotective layer), and/or an oxygendomain (not shown), such as described in more detail in the above-citedU.S. patent publications. However, it is understood that a sensingmembrane modified for other sensors, for example, by including fewer oradditional domains is within the scope of some embodiments. In someembodiments, one or more domains of the sensing membranes are formedfrom materials such as silicone, polytetrafluoroethylene,polyethylene-co-tetrafluoroethylene, polyolefin, polyester,polycarbonate, biostable polytetrafluoroethylene, homopolymers,copolymers, terpolymers of polyurethanes, polypropylene (PP),polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polybutyleneterephthalate (PBT), polymethylmethacrylate (PMMA), polyether etherketone (PEEK), polyurethanes, cellulosic polymers, poly(ethylene oxide),poly(propylene oxide) and copolymers and blends thereof, polysulfonesand block copolymers thereof including, for example, di-block,tri-block, alternating, random and graft copolymers. U.S. PatentPublication No. US-2005-024579912-A1 describes biointerface and sensingmembrane configurations and materials that may be applied to someembodiments.

In some embodiments, the sensing membrane can be deposited on theelectroactive surfaces of the electrode material using known thin orthick film techniques (for example, spraying, electro-depositing,dipping, or the like). It is noted that the sensing membrane thatsurrounds the working electrode does not have to be the same structureas the sensing membrane that surrounds a reference electrode, etc. Forexample, the enzyme domain deposited over the working electrode does notnecessarily need to be deposited over the reference and/or counterelectrodes.

Membrane System

Generally, analyte sensors of the preferred embodiments comprise amembrane system, such as those illustrated in FIGS. 2E and 2F.Preferably, a membrane system is deposited over at least a portion ofthe electroactive surfaces of the sensor (working electrode(s) andoptionally reference electrode) and provides protection of the exposedelectrode surface from the biological environment, diffusion resistance(limitation) of the analyte if needed, a catalyst for enabling anenzymatic reaction, limitation or blocking of interferents, and/orhydrophilicity at the electrochemically reactive surfaces of the sensorinterface. Some examples of suitable membrane systems are described inU.S. Patent Publication No. US-2005-0245799-A1.

In general, the membrane system 32 includes a plurality of domains, forexample, one or more of an electrode domain 43, an interference domain44, an enzyme domain 46 (for example, including glucose oxidase), and aresistance domain 48, as shown in FIGS. 2B and 2C, and can include ahigh oxygen solubility domain, a bioprotective domain and/or a celldisruptive domain, such as is described in more detail in U.S. PatentPublication No. US-2005-0245799-A1, and such as are described in moredetail below. While the embodiment illustrated in FIGS. 2E and 2F showsthe interference domain between the electrode domain and the enzymedomain, the interference domain can be disposed more proximal or moredistal to the electroactive surfaces. For example, in some embodiments,the interference domain 44 is more distal to the electroactive surfacesthan the enzyme domain. In some embodiments, the interference domain isthe most distal layer/domain of the membrane system, relative to theelectroactive surfaces. In some embodiments, the interference domain canbe the most proximal domain/layer, relative to the electroactivesurfaces. In still other embodiments, the interference can be combinedwith one or more other membrane domains/layers. For example, in someembodiments, the interference domain and the resistance domain arecombined into a single domain that provides both interference blockingand control of analyte flux. One skilled in the art appreciates that awide variety of configurations and combinations encompassed by thepreferred embodiments.

The membrane system can be deposited on the exposed electroactivesurfaces using known thin film techniques (for example, vapordeposition, spraying, electro-depositing, dipping, or the like). Inalternative embodiments, however, other deposition processes (e.g.,physical and/or chemical vapor deposition processes) can be useful forproviding one or more of the insulating and/or membrane layers,including ultrasonic vapor deposition, electrostatic deposition,evaporative deposition, deposition by sputtering, pulsed laserdeposition, high velocity oxygen fuel deposition, thermal evaporatordeposition, electron beam evaporator deposition, deposition by reactivesputtering molecular beam epitaxy, atmospheric pressure chemical vapordeposition (CVD), atomic layer CVD, hot wire CVD, low-pressure CVD,microwave plasma-assisted CVD, plasma-enhanced CVD, rapid thermal CVD,remote plasma-enhanced CVD, ultra-high vacuum CVD, and ion implantationfor example. However, the membrane system can be disposed over (ordeposited on) the electroactive surfaces using any known method, as willbe appreciated by one skilled in the art.

In some embodiments, one or more domains of the membrane systems areformed from materials such as silicone, polytetrafluoroethylene,polyethylene-co-tetrafluoroethylene, polyolefin, polyester,polycarbonate, biostable polytetrafluoroethylene, homopolymers,copolymers, terpolymers of polyurethanes, polypropylene (PP),polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polybutyleneterephthalate (PBT), polymethylmethacrylate (PMMA), polyether etherketone (PEEK), polyurethanes, cellulosic polymers, polysulfones andblock copolymers thereof including, for example, di-block, tri-block,alternating, random and graft copolymers. U.S. Patent Publication No.US-2005-0245799-A1 describes biointerface and membrane systemconfigurations and materials that may be applied to the preferredembodiments.

The function of a membrane system 32 domain is dependent upon acombination of factors, such as but not limited to the domain thickness,the domain composition, the number of layers in the domain (or in themembrane as a whole) and the way the layers are applied (e.g., severalthin layers may give better/complete coverage where one thick layer maynot completely cover). In preferred embodiments, these factors areconfigured to provide a membrane system that renders the sensor'ssignal-to-noise ratio would be rendered substantially unaffected bynon-constant noise. The sensor's signal-to-noise ratio can by renderedsubstantially unaffected by non-constant noise either by substantiallyincreasing the analyte component (e.g., without a corresponding increasein the noise component) or by substantially reducing the noise component(e.g., without substantially reducing the analyte component).

Accordingly, in some preferred embodiments, membrane system 32 isconfigured to render the sensor's signal-to-noise ratio substantiallyunaffected by non-constant noise by substantially increasing thediffusion of glucose therein, while diffusion of at least oneinterferent (e.g., H₂O₂ formed outside the membrane system) into themembrane system is substantially unaffected, such that the analytecomponent is at least 80% of the total signal. Alternatively oradditionally, in some preferred embodiments, the membrane system isconfigured to render the sensor's signal-to-noise ratio to besubstantially unaffected by non-constant noise by reducing the noisecomponent (e.g., non-constant noise) of the total signal without acorresponding reduction in the analyte component. In some preferredembodiments, the membrane system is configured to both increase theanalyte signal component and reduce the non-constant noise signalcomponent.

In one preferred embodiment, an analyte sensor includes a membranesystem disposed over an electrode, such as the working electrode,wherein the membrane system is configured for inactivation ofelectroactive species that can interfere with the analyte signal. Inother preferred embodiments, the membrane system is configured tosubstantially consume at least one electroactive compound (thatinterferes with the analyte signal) diffusing therein, such that thecompound is substantially prevented from reaching the electroactivesurface. The term “consumed” as used herein is a broad term and is usedin its ordinary sense, including, without limitation, to render theinterferent substantially non-reactive with the electroactive surfaceand/or the voltage potential of the sensor, such as by oxidation orreduction of the interferent. For example, the membrane system caninteract with the interferent such that the interferent's redoxpotential is changed and the interferent is substantially unable to beoxidized and/or reduced when the interferent contacts the electroactivesurface, at the voltage potential at which the sensor operates. Invarious embodiments, the membrane system is configured to substantiallyconsume at least one interfering species by at least one of thefollowing: a torturous diffusion path, a thickness of from about 2 μm toabout 100 μm or more, a peroxidase, oxidase, catalase and/or a Hemecompound, and the like, which are described in more detail elsewhereherein. In some preferred embodiments, the membrane thickness is fromabout 5 μm to about 50 μm.

Electrode Domain

In selected embodiments, the membrane system comprises an electrodedomain. The electrode domain 43 is provided to ensure that anelectrochemical reaction occurs between the electroactive surfaces ofthe working electrode and the reference electrode, and thus theelectrode domain 43 is preferably situated more proximal to theelectroactive surfaces than the interference and/or enzyme domain.Preferably, the electrode domain includes a coating that maintains alayer of water at the electrochemically reactive surfaces of the sensor.In other words, the electrode domain is present to provide anenvironment between the surfaces of the working electrode and thereference electrode, which facilitates an electrochemical reactionbetween the electrodes. For example, a humectant in a binder materialcan be employed as an electrode domain; this allows for the fulltransport of ions in the aqueous environment. The electrode domain canalso assist in stabilizing the operation of the sensor by acceleratingelectrode start-up and drifting problems caused by inadequateelectrolyte. The material that forms the electrode domain can alsoprovide an environment that protects against pH-mediated damage that canresult from the formation of a large pH gradient due to theelectrochemical activity of the electrodes.

In one embodiment, the electrode domain 43 includes a flexible,water-swellable, hydrogel film having a “dry film” thickness of fromabout 0.05 microns or less to about 20 microns or more, more preferablyfrom about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1,1.5, 2, 2.5, 3, or 3.5 microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and more preferably stillfrom about 3, 2.5, 2, or 1 microns, or less to about 3.5, 4, 4.5, or 5microns or more. “Dry film” thickness refers to the thickness of a curedfilm cast from a coating formulation by standard coating techniques.

In certain embodiments, the electrode domain 43 is formed of a curablemixture of a urethane polymer and a hydrophilic polymer. Particularlypreferred coatings are formed of a polyurethane polymer havingcarboxylate or hydroxyl functional groups and non-ionic hydrophilicpolyether segments, wherein the polyurethane polymer is crosslinked witha water-soluble carbodiimide (e.g.,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)) in the presence ofpolyvinylpyrrolidone and cured at a moderate temperature of about 50° C.

In some preferred embodiments, the electrode domain 43 is formed from ahydrophilic polymer (e.g., a polyamide, a polylactone, a polyimide, apolylactam, a functionalized polyamide, a functionalized polylactone, afunctionalized polyimide, a functionalized polylactam or a combinationthereof) that renders the electrode domain substantially morehydrophilic than an overlying domain, (e.g., interference domain, enzymedomain). In some embodiments, the electrode domain is formedsubstantially entirely and/or primarily from a hydrophilic polymer. Insome embodiments, the electrode domain is formed substantially entirelyfrom PVP. In some embodiments, the electrode domain is formed entirelyfrom a hydrophilic polymer. Useful hydrophilic polymers include but arenot limited to poly-N-vinylpyrrolidone (PVP), poly-N-vinyl-2-piperidone,poly-N-vinyl-2-caprolactam, poly-N-vinyl-3-methyl-2-caprolactam,poly-N-vinyl-3-methyl-2-piperidone, poly-N-vinyl-4-methyl-2-piperidone,poly-N-vinyl-4-methyl-2-caprolactam, poly-N-vinyl-3-ethyl-2-pyrrolidone,poly-N-vinyl-4,5-dimethyl-2-pyrrolidone, polyvinylimidazole,poly-N,N-dimethylacrylamide, polyvinyl alcohol (PVA), polyHEME,Poly-methyl methacrylate (PMMA), ethylene vinyl acetate (EVA), PGA-PEG,polyanhydrides, polyacrylic acid, polyethylene oxide,poly-2-ethyl-oxazoline, copolymers thereof and mixtures thereof. A blendof two or more hydrophilic polymers is preferred in some embodiments. Insome preferred embodiments, the hydrophilic polymer(s) is notcrosslinked. In alternative embodiments, crosslinking is preferred, suchas by adding a crosslinking agent, such as but not limited to EDC, or byirradiation at a wavelength sufficient to promote crosslinking betweenthe hydrophilic polymer molecules, which is believed to create a moretortuous diffusion path through the domain.

An electrode domain formed from a hydrophilic and/or conductive polymer(e.g., PVP and buffer) has been shown to substantially reduce break-intime of analyte sensors; for example, a glucose sensor utilizing acellulosic-based interference domain such as described in more detailelsewhere herein. In some embodiments, a uni-component electrode domainformed from a single hydrophilic polymer (e.g., PVP) has been shown tosubstantially reduce break-in time of a glucose sensor to less thanabout 2 hours, less than about 1 hour, less than about 20 minutes and/orsubstantially immediately. Generally, sensor break-in is the amount oftime required (after implantation) for the sensor signal to becomesubstantially representative of the analyte concentration. Sensorbreak-in includes both membrane break-in and electrochemical break-in,which are described in more detail elsewhere herein. In someembodiments, break-in time is less than about 2 hours. In otherembodiments, break-in time is less than about 1 hour. In still otherembodiments, break-in time is less than about 30 minutes, less thanabout 20 minutes, less than about 15 minutes, less than about 10minutes, or less. In a preferred embodiment, sensor break-in occurssubstantially immediately. Advantageously, in embodiments wherein thebreak-in time is about 0 minutes (substantially immediately), the sensorcan be inserted and begin providing substantially accurate analyte(e.g., glucose) concentrations almost immediately post-insertion, forexample, wherein membrane break-in does not limit start-up time.

While not wishing to be bound by theory, it is believed that providingan electrode domain that is substantially more hydrophilic than the nextmore distal membrane layer or domain (e.g., the overlaying domain; thelayer more distal to the electroactive surface than the electrodedomain, such as an interference domain or an enzyme domain) reduces thebreak-in time of an implanted sensor, by increasing the rate at whichthe membrane system is hydrated by the surrounding host tissue. Whilenot wishing to be bound by theory, it is believed that, in general,increasing the amount of hydrophilicity of the electrode domain relativeto the overlaying layer (e.g., the distal layer in contact withelectrode domain, such as the interference domain, enzyme domain, etc.)increases the rate of water absorption, resulting in reduced sensorbreak-in time. The hydrophilicity of the electrode domain can besubstantially increased by the proper selection of hydrophilic polymers,based on their hydrophilicity relative to each other and relative to theoverlaying layer (e.g., cellulosic-based interference domain), withpreferred polymers being substantially more hydrophilic than theoverlaying layer. In one exemplary embodiment, PVP forms the electrodedomain, the interference domain is formed from a blend of cellulosicderivatives, such as but not limited to cellulose acetate butyrate andcellulose acetate; it is believed that since PVP is substantially morehydrophilic than the cellulosic-based interference domain, the PVPrapidly draws water into the membrane to the electrode domain, andenables the sensor to function with a desired sensitivity and accuracyand starting within a substantially reduced time period afterimplantation. Reductions in sensor break-in time reduce the amount oftime a host must wait to obtain sensor readings, which is particularlyadvantageous not only in ambulatory applications, but particularly inhospital settings where time is critical. In some alternativeembodiments, a hydrophilic (e.g., PVP) electrode domain can be formedunder a silicone-pluronic polymer blend interference domain, such thatthe sensor break-in time is substantially reduced.

While not wishing to be bound by theory, it is believed that when thewater absorption of the overlying domain (e.g., the domain overlying theelectrode domain) is less than the water absorption of the electrodedomain (e.g., during membrane equilibration), then the difference inwater absorption between the two domains will drive membraneequilibration and thus membrane break-in. Namely, increasing thedifference in hydrophilicity (e.g., between the two domains) results inan increase in the rate of water absorption, which, in turn, results ina decrease in membrane break-in time and/or sensor break-in time.

Generally, the molecular weight of the analyte is substantially higherthan that of many electroactive species that can interfere with theanalyte signal, for example, reactive oxygen and nitrogen species. Asone example, the molecular weight of glucose is 180 g/mole, while themolecular weight of H₂O₂ is 34.02 g/mole. Diffusion of a moleculethrough the membrane system is substantially regulated by the membrane'sporosity (e.g., the size of the pores) and hydrophilicity. Since smallmolecules, such as H₂O₂ and reactive oxygen and nitrogen species, etc.,generally diffuse through many membrane systems at substantially theirmaximum rates (e.g., due to their small size), many membrane systemconfiguration modifications have substantially little affect on theirdiffusion rates. In contrast, due to its larger size, the diffusion ofthe analyte (e.g., glucose) through the membrane system is substantiallyslowed. It is believed that increasing the diffusion rate of the analyte(through the membrane system) does not substantially affect thediffusion rate the above-described small molecules. However, increasingthe difference in hydrophilicity (e.g., between the two domains)substantially increases the diffusion rate of the analyte, without anequivalent increase in the diffusion of small molecules, such that theanalyte component (e.g., of the total signal) is increased, while thenoise component (e.g., of the total signal) remains substantiallyunchanged, which adjusts (e.g., increases) the signal-to-noise ratio.The adjusted signal-to-noise ratio resulting from inclusion of ahydrophilic electrode domain (e.g., 2 x PVP in some embodiments)increases sensor sensitivity and reduces sensor error, whichadvantageously adjusts the signal to noise ratio of the sensor overwhich it is located.

As discussed elsewhere herein, the relative hydrophilicity of theelectrode domain 43 as compared to the overlying domain(s) can bemodulated by the selection of more hydrophilic materials for formationof the electrode domain (and/or more hydrophobic materials for theoverlying domain(s)). For example, an electrode domain with hydrophilicpolymer capable of absorbing larger amounts of water can be selectedinstead of a second hydrophilic polymer that is capable of absorbingless water than the first hydrophilic polymer. In some embodiments, thewater content difference between the electrode domain and the overlyingdomain (e.g., during or after membrane equilibration) is from about 1%or less to about 90% or more. In other embodiments, the water contentdifference between the electrode domain and the overlying domain is fromabout 10% or less to about 80% or more. In still other embodiments, thewater content difference between the electrode domain and the overlyingdomain is from about 30% or less to about 60% or more. In preferredembodiments, the electrode domain absorbs 5 wt. % or less to 95 wt. % ormore water, preferably 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 wt. % toabout 55, 60, 65, 70, 75, 80, 85, 90 or 95 wt. % water than the adjacent(overlying) domain (e.g., the domain that is more distal to theelectroactive surface than the electrode domain).

In another example, the rate of water absorption by a polymer can beaffected by other factors, such as but not limited to the polymer'smolecular weight. For example, the rate of water absorption by PVP isdependent upon its molecular weight, which is typically from about40-kDa or less to about 360-kDa or more; with a lower molecular weightPVP (e.g., 40-kDa) absorbing water faster than a higher molecular weightPVP. Accordingly, modulating factors, such as molecular weight, thataffect the rate of water absorption by a polymer, can promote the properselection of materials for electrode domain fabrication. In oneembodiment, a lower molecular weight PVP is selected, to reduce break-intime.

Preferably, the electrode domain is deposited by known thin filmdeposition techniques (e.g., spray coating or dip-coating theelectroactive surfaces of the sensor). In some embodiments, theelectrode domain is formed by dip-coating the electroactive surfaces inan electrode domain solution (e.g., 5, 10, 15, 20, 25 or 30% or more PVPin deionized water) and curing the domain for a time of from about 15minutes to about 30 minutes at a temperature of from about 40° C. toabout 55° C. (and can be accomplished under vacuum (e.g., 20 to 30mmHg)). In embodiments wherein dip-coating is used to deposit theelectrode domain, a preferred insertion rate of from about 1 inch toabout 3 inches per minute into the electrode domain solution, with apreferred dwell time of from about 0.5 minutes to about 2 minutes in theelectrode domain solution, and a preferred withdrawal rate of from about0.25 inches to about 2 inches per minute from the electrode domainsolution provide a functional coating. However, values outside of thoseset forth above can be acceptable or even desirable in certainembodiments, for example, depending upon solution viscosity and solutionsurface tension, as is appreciated by one skilled in the art. In oneembodiment, the electroactive surfaces of the electrode system aredip-coated one time (one layer) and cured at 50° C. under vacuum for 20minutes. In another embodiment, the electroactive surfaces of theelectrode system is dip-coated and cured at 50° C. under vacuum for 20minutes a first time, followed by dip coating and curing at 50° C. undervacuum for 20 minutes a second time (two layers). In still otherembodiments, the electroactive surfaces can be dip-coated three or moretimes (three or more layers). In other embodiments, the 1, 2, 3 or morelayers of PVP are applied to the electroactive surfaces by spray coatingor vapor deposition. In some embodiments, a crosslinking agent (e.g.,EDC) can be added to the electrode domain casting solution to promotecrosslinking within the domain (e.g., between electrode domain polymercomponents, latex, etc.). In some alternative embodiments however, nocrosslinking agent is used and the electrode domain is not substantiallycrosslinked.

In some embodiments, the deposited PVP electrode domain 43 has a “dryfilm” thickness of from about 0.05 microns or less to about 20 micronsor more, more preferably from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3,0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 microns to about 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, andmore preferably still from about 2, 2.5 or 3 microns to about 3.5, 4,4.5, or 5 microns.

Although an independent electrode domain 43 is described herein, in someembodiments sufficient hydrophilicity can be provided in theinterference domain and/or enzyme domain (the domain adjacent to theelectroactive surfaces) so as to provide for the full transport of ionsin the aqueous environment (e.g. without a distinct electrode domain).In these embodiments, an electrode domain is not necessary.

Interference Domain

In some embodiments, the membrane system 34 comprises an interferencedomain 44 configured to substantially reduce and/or block diffusion ofone or more noise-causing interferents into the membrane system, andthereby increase the signal-to-noise ratio of the sensor. In someembodiments, the interference domain 44 is a component of the membranesystem, such as shown in FIGS. 2E and 2F. However, the interferencedomain can be disposed at any level (e.g., layer or domain) of themembrane system (e.g., more proximal or more distal to the electroactivesurfaces than as shown in FIGS. 2E and 2F). In some other embodiments,the interference domain is combined with an additional membrane domain,such as the resistance domain or the enzyme domain.

As discussed elsewhere herein, noise can occur during the first fewhours or days after sensor implantation, such as during periods ofinactivity (e.g., intermittent, sedentary noise), and is believed to becaused by a local increase in interferants (e.g., electroactivemetabolites) that disrupts sensor function, resulting in apparentglucose signals that are generally unrelated to the host's glucoseconcentration. While not wishing to be bound by theory, it is believedthat the noise intensity and/or number of intermittent, sedentary noiseoccurrences can be reduced or eliminated by reducing the localconcentration of interferants, such as by incorporation of aninterference domain 44 into the membrane system 34. In general, the term“interference domain” includes any noise-reducing mechanism thatsubstantially blocks, reduces, eliminates, reacts with, or otherwisekeeps an interferant from reacting at the working electrode(s).“Noise-reducing mechanisms” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to any sensor system componentor configuration that reduces and/or eliminates noise on the sensorsignal. Some noise-reducing mechanisms include but are not limited toelectrode configurations (e.g., two or more working electrodes),membrane configurations (e.g., interference domain), algorithmicconfigurations (e.g., signal processing to remove an identified noisecomponent of the signal), and the like. Additionally, the noise-reducingmechanisms described herein, including structures, membrane materials,bioactive agents, and the like, which can reduce the effect ofinterfering species (noise) on the sensor signal, can be considered atleast a part of an “interference domain.” Some examples of interferencedomain structures are described herein in this section entitled,“Interference Domain.” However, other known interference domainstructures can be implemented with the sensors described herein. Whilethe embodiments shown in FIGS. 2E and 2F show the interference domain 44located between the electrode and enzyme domains, the interferencedomain can be disposed at any level of the membrane system (e.g., moreproximal or more distal to the electroactive surfaces). For example, theinterference domain can be disposed between the enzyme domain and theresistance domain, between the electroactive surfaces and the electrodedomain, as the most exterior membrane domain, etc. In some embodiments,any domain of the membrane system can be configured to function as aninterference domain or combined with the interference domain. Forexample, the enzyme domain and interference domain can be combined intoan enzyme-interference domain that performs the functions of an enzymedomain and an interference domain.

In one preferred embodiment, the membrane system includes aninterference domain that is configured to substantially reduce noise(e.g., non-constant noise) caused by one or more endogenous or exogenousinterferents. In preferred embodiments, the signal-to-noise ratio can beadjusted (e.g., increased) by incorporation of an interference domain ofthe preferred embodiments onto a sensor. In some preferred embodiments,the interference domain is configured such that the analyte component isat least about 80% of the total signal for a period of at least aboutone day. In some preferred embodiments, the interference domain isconfigured such that the non-constant noise component is less than about20% of the total signal for at least about one day.

As illustrated in FIGS. 2E and 2F, the membrane system 32 of thepreferred embodiments includes an interference domain 44. In somepreferred embodiments, an interference domain is provided thatsubstantially restricts or blocks the flow of one or more interferingspecies therethrough. In some embodiments, the interference domain canbe configured to reduce noise (and adjust the signal-to-noise ratio)using, one, two or more noise-reducing mechanisms. For example, in someembodiments, the interference domain is configured to substantiallyblock passage of at least one interfering species into the membranesystem. In some embodiments, the interference domain is configured tosubstantially reduce the concentration of at least one interferent. Forexample, the interferent can be diluted, such as by promoting anincreased fluid bulk and/or formation of a fluid pocket around thesensor. Alternatively or additionally, the interferent concentration canbe substantially reduced by configuring the interference domain toincrease bulk fluid flow (e.g., which carries interferents away via thelymph system). In other embodiments, the interference domain isconfigured to oxidize and/or reduce an interferent, such that theinterferent no longer substantially affects the sensor. In someembodiments, the interference domain is configured to reduce thenon-constant noise (and adjust the signal-to-noise ratio) by combiningtwo or more noise-reducing mechanisms, as described below. Some knowninterfering species for a glucose sensor, as described in more detailherein, include acetaminophen, ascorbic acid, bilirubin, cholesterol,creatinine, dopamine, ephedrine, ibuprofen, L-dopa, methyldopa,salicylate, tetracycline, tolazamide, tolbutamide, triglycerides, anduric acid. In some embodiments, the interference domain of the preferredembodiments is less permeable to one or more of the interfering speciesthan to the measured species, e.g., the product of an enzymatic reactionthat is measured at the electroactive surface(s), such as but notlimited to H₂O₂.

Cellulosic Polymer Materials

In one embodiment, the interference domain 44 is formed from one or morecellulosic derivatives. Cellulosic derivatives can include, but are notlimited to, cellulose esters and cellulose ethers. In general,cellulosic derivatives include polymers such as cellulose acetate,cellulose acetate butyrate, 2-hydroxyethyl cellulose, cellulose acetatephthalate, cellulose acetate propionate, cellulose acetate trimellitate,and the like, as well as their copolymers and terpolymers with othercellulosic or non-cellulosic monomers. Cellulose is a polysaccharidepolymer of β-D-glucose. While cellulosic derivatives are generallypreferred, other polymeric polysaccharides having similar properties tocellulosic derivatives can also be employed in the preferredembodiments.

In one preferred embodiment, the interference domain 44 is formed fromcellulose acetate butyrate. Cellulose acetate butyrate with a molecularweight of from about 10,000 daltons to about 75,000 daltons, preferablyfrom about 15,000, 20,000, or 25,000 daltons to about 50,000, 55,000,60,000, 65,000, or 70,000 daltons, and more preferably about 20,000daltons is employed. In certain embodiments, however, higher or lowermolecular weights can be preferred. In some embodiments, a blend of twoor more cellulose acetate butyrates having different molecular weightsis preferred. While a “blend” as defined herein (a composition of two ormore substances that are not substantially chemically combined with eachother and are capable of being separated) is generally preferred, incertain embodiments a single polymer incorporating differentconstituents (e.g., separate constituents as monomeric units and/orsubstituents on a single polymer chain) can be employed instead.Additionally, a casting solution or dispersion of cellulose acetatebutyrate at a weight percent of from about 5% to about 25%, preferablyfrom about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or 15% to about16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%, and more preferablyfrom about 5% to about 15% is preferred. Preferably, the castingsolution includes a solvent or solvent system, for example anacetone:ethanol solvent system. Higher or lower concentrations can bepreferred in certain embodiments. In alternative embodiments, a singlesolvent (e.g., acetone) is used to form a symmetrical membrane domain. Asingle solvent is used in casting solutions for forming symmetricmembrane layer(s). A plurality of layers of cellulose acetate butyratecan be advantageously combined to form the interference domain in someembodiments, for example, three layers can be employed. It can bedesirable to employ a mixture of cellulose acetate butyrate componentswith different molecular weights in a single solution, or to depositmultiple layers of cellulose acetate butyrate from different solutionscomprising cellulose acetate butyrate of different molecular weights,different concentrations, and/or different chemistries (e.g., functionalgroups). It can also be desirable to include additional substances inthe casting solutions or dispersions, e.g., functionalizing agents,crosslinking agents, other polymeric substances, substances capable ofmodifying the hydrophilicity/hydrophobicity of the resulting layer, andthe like.

In one alternative embodiment, the interference domain 44 is formed fromcellulose acetate. Cellulose acetate with a molecular weight of fromabout 30,000 daltons or less to about 100,000 daltons or more,preferably from about 35,000, 40,000, or 45,000 daltons to about 55,000,60,000, 65,000, 70,000, 75,000, 80,000, 85,000, 90,000, or 95,000daltons, and more preferably about 50,000 daltons is preferred. In someembodiments, a blend of two or more cellulose acetates having differentmolecular weights is preferred. Additionally, a casting solution ordispersion of cellulose acetate at a weight percent of from about 3% toabout 10%, preferably from about 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, or6.5% to about 7.5%, 8.0%, 8.5%, 9.0%, or 9.5%, and more preferably about8% is preferred. In certain embodiments, however, higher or lowermolecular weights and/or cellulose acetate weight percentages can bepreferred. It can be desirable to employ a mixture of cellulose acetateswith molecular weights in a single solution, or to deposit multiplelayers of cellulose acetate from different solutions comprisingcellulose acetates of different molecular weights, differentconcentrations, or different chemistries (e.g., functional groups). Itcan also be desirable to include additional substances in the castingsolutions or dispersions such as described in more detail above.

In addition to forming an interference domain from only celluloseacetate(s) or only cellulose acetate butyrate(s), the interferencedomain 44 can be formed from combinations or blends of cellulosicderivatives, such as but not limited to cellulose acetate and celluloseacetate butyrate, or combinations of layer(s) of cellulose acetate andlayer(s) of cellulose acetate butyrate. In some embodiments, a blend ofcellulosic derivatives (for formation of an interference domain)includes up to about 10 wt. % or more of cellulose acetate. For example,about 1, 2, 3, 4, 5, 6, 7, 8, 9 wt. % or more cellulose acetate ispreferred, in some embodiments. In some embodiments, the cellulosicderivatives blend includes from about 90 wt. % or less to about 100 wt.% cellulose acetate butyrate. For example, in some embodiments, theblend includes about 91, 92, 93, 94, 95, 96, 97, 98 or 99 wt. %cellulose acetate butyrate. In some embodiments, the cellulosicderivative blend includes from about 1.5, 2.0, 2.5, 3.0 or 3.5 wt. %cellulose acetate to about 98.5, 98.0, 97.5, 97.0 or 96.5 wt. %cellulose acetate butyrate. In other embodiments, the blend includesfrom about 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 or 8 wt. % cellulose acetateto about 96, 95.5, 95, 94.5, 94, 93.3, 93, 92.5 or 92 wt. % celluloseacetate butyrate. In still other embodiments, the blend includes fromabout 8.5, 9.0, 9.5, 10.0, 10.5 or 11.0 wt. % cellulose acetate to about91.5, 91.0, 90.5, 90, 89.5 or 89 wt. % cellulose acetate butyrate.

In some embodiments, preferred blends of cellulose acetate and celluloseacetate butyrate contain from about 1.5 parts or less to about 60 partsor more cellulose acetate butyrate to one part of cellulose acetate. Insome embodiments, a blend contains from about 2 parts to about 40 partscellulose acetate butyrate to one part cellulose acetate. In otherembodiments, about 4, 6, 8, 10, 12, 14, 16, 18 or 20 parts celluloseacetate butyrate to one part cellulose acetate is preferred forformation of the interference domain 26. In still other embodiments, ablend having from 22, 24, 26, 28, 30, 32, 34, 36 or 38 parts celluloseacetate butyrate to one part cellulose acetate is preferred. As isdiscussed elsewhere herein, cellulose acetate butyrate is relativelymore hydrophobic than cellulose acetate. Accordingly, the celluloseacetate/cellulose acetate butyrate blend contains substantially morehydrophobic than hydrophilic components.

Cellulose acetate butyrate is a cellulosic polymer having both acetyland butyl groups, in addition to hydroxyl groups. Acetyl groups are morehydrophilic than butyl groups, and hydroxyl groups are more hydrophilicthan both acetyl and butyl groups. Accordingly, the relative amounts ofacetyl, butyl and hydroxyl groups can be used to modulate thehydrophilicity/hydrophobicity of the cellulose acetate butyrate of thecellulose acetate/cellulose acetate butyrate blend. A cellulose acetatebutyrate can be selected based on the compound's relative amounts ofacetate, butyrate and hydroxyl groups; and a cellulose acetate can beselected based on the compounds relative amounts of acetate and hydroxylgroups. For example, in some embodiments, a cellulose acetate butyratehaving about 35% or less acetyl groups, about 10% to about 25% butylgroups, and hydroxyl groups making up the remainder is preferred forformation of the interference domain 44. In other embodiments acellulose acetate butyrate having from about 25% to about 34% acetylgroups and from about 15 to about 20% butyl groups is preferred. Instill other embodiments, the preferred cellulose acetate butyratecontains from about 28% to about 30% acetyl groups and from about 16 toabout 18% butyl groups. In yet another embodiment, the cellulose acetatebutyrate can have no acetate groups and from about 20% to about 60%butyrate groups. In yet another embodiment, the cellulose acetatebutyrate has about 55% butyrate groups and no acetate groups.

While an asymmetric interference domain can be used in some alternativeembodiments, a symmetrical interference domain 44 (e.g., ofcellulosic-derivative blends, such as but not limited to blends ofcellulose acetate components and cellulose acetate butyrate components)is preferred in some embodiments. Symmetrical membranes are uniformthroughout their entire structure, without gradients of pore densitiesor sizes, or a skin on one side but not the other, for example. Invarious embodiments, a symmetrical interference domain can be formed bythe appropriate selection of a solvent (e.g., no anti-solvent is used),for making the casting solution. Appropriate solvents include solventsbelonging to the ketone family that are able to solvate the celluloseacetate and cellulose acetate butyrate. The solvents include but are notlimited to acetone, methyl ethyl ketone, methyl n-propyl ketone,cyclohexanone, and diacetone alcohol. Other solvents, such as furans(e.g., tetra-hydro-furan and 1,4-dioxane), may be preferred in someembodiments. In one exemplary embodiment, from about 7 wt. % to about 9wt. % solids (e.g., a blend of cellulosic derivatives, such as celluloseacetate and cellulose acetate butyrate) are blended with a singlesolvent (e.g., acetone), to form the casting solution for a symmetricalinterference domain. In another embodiment, from about 10% to about 15%solids are blended with acetone to form the casting solution. In yetanother embodiment, from about 16 to about 18% solids are blended withacetone to form the casting solution. A relatively lower or greaterweight percent of solids is preferred to form the casting solution, insome embodiments.

The casting solution can be applied either directly to the electroactivesurface(s) of the sensor or on top of an electrode domain layer (ifincluded in the membrane system). The casting solution can be appliedusing any known thin film technique, as discussed elsewhere herein.Additionally, in various embodiments, a symmetrical interference domain44 includes at least one layer; and in some embodiments, two, three ormore layers are formed by the sequential application and curing of thecasting solution.

The concentration of solids in the casting solution can be adjusted todeposit a sufficient amount of solids on the electrode in one layer(e.g., in one dip or spray) to form a membrane layer with sufficientblocking ability, such that the equivalent glucose signal of aninterferent (e.g., compounds with an oxidation or reduction potentialthat overlaps with that of the measured species (e.g., H₂O₂)), measuredby the sensor, is about 60 mg/dL or less. For example, in someembodiments, the casting solution's percentage of solids is adjustedsuch that only a single layer (e.g., dip one time) is required todeposit a sufficient amount of the cellulose acetate/cellulose acetatebutyrate blend to form a functional symmetric interference domain thatsubstantially blocks passage therethrough of at least one interferent,such as but not limited to acetaminophen, ascorbic acid, dopamine,ibuprofen, salicylic acid, tolbutamide, tetracycline, creatinine, uricacid, ephedrine, L-dopa, methyl dopa and tolazamide. In someembodiments, the amount of interference domain material deposited by assingle dip is sufficient to reduce the equivalent glucose signal of theinterferant (e.g., measured by the sensor) to about 60 mg/dl or less. Inpreferred embodiments, the interferent's equivalent glucose signalresponse (measured by the sensor) is 50 mg/dl or less. In more preferredembodiments, the interferent produces an equivalent glucose signalresponse of 40 mg/dl or less. In still more preferred embodiments, theinterferent produces an equivalent glucose signal response of less thanabout 30, 20 or 10 mg/dl. In one exemplary embodiment, the interferencedomain is configured to substantially block acetaminophen passagetherethrough, wherein the equivalent glucose signal response of theacetaminophen is less than about 30 mg/dl.

In alternative embodiments, the interference domain is configured tosubstantially block a therapeutic dose of acetaminophen. The term“therapeutic dose” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to the quantity of any substance required toeffect the cure of a disease, to relieve pain, or that will correct themanifestations of a deficiency of a particular factor in the diet, suchas the effective dose used with therapeutically applied compounds, suchas drugs. For example, a therapeutic dose of acetaminophen can be anamount of acetaminophen required to relieve headache pain or reduce afever. As a further example, 1,000 mg of acetaminophen taken orally,such as by swallowing two 500 mg tablets of acetaminophen, is thetherapeutic dose frequently taken for headaches. In some embodiments,the interference membrane is configured to block a therapeutic dose ofacetaminophen, wherein the equivalent glucose signal response of theacetaminophen is less than about 60 mg/dl. In a preferred embodiment,the interference membrane is configured to block a therapeutic dose ofacetaminophen, wherein the equivalent glucose signal response of theacetaminophen is less than about 40 mg/dl. In a more preferredembodiment, the interference membrane is configured to block atherapeutic dose of acetaminophen, wherein the equivalent glucose signalresponse of the acetaminophen is less than about 30 mg/dl.

While not wishing to be bound by theory, it is believed that, withrespect to symmetrical cellulosic-based membranes, there is an inverselyproportional balance between interferent blocking and analytesensitivity. Namely, changes to the interference domain configurationthat increase interferent blocking can result in a correspondingdecrease in sensor sensitivity in some embodiments. Sensor sensitivityis discussed in more detail elsewhere herein. It is believed that thebalance between interferent blocking and sensor sensitivity is dependentupon the relative proportions of hydrophobic and hydrophilic componentsof the membrane layer (e.g., the interference domain), with sensorshaving more hydrophobic interference domains having increasedinterferent blocking but reduced sensitivity; and sensors having morehydrophilic interference domains having reduced interferent blocking butincreased sensitivity. It is believed that the hydrophobic andhydrophilic components of the interference domain can be balanced, topromote a desired level of interferent blocking while at the same timemaintaining a desired level of analyte sensitivity. The interferencedomain hydrophobe-hydrophile balance can be manipulated and/ormaintained by the proper selection and blending of the hydrophilic andhydrophobic interference domain components (e.g., cellulosic derivativeshaving acetyl, butyryl, propionyl, methoxy, ethoxy, propoxy, hydroxyl,carboxymethyl, and/or carboxyethyl groups). For example, celluloseacetate is relatively more hydrophilic than cellulose acetate butyrate.In some embodiments, increasing the percentage of cellulose acetate (orreducing the percentage of cellulose acetate butyrate) can increase thehydrophilicity of the cellulose acetate/cellulose acetate butyrateblend, which promotes increased permeability to hydrophilic species,such as but not limited to glucose, H₂O₂ and some interferents (e.g.,acetaminophen). In another embodiment, the percentage of celluloseacetate butyrate is increased to increase blocking of interferants, butless permeability to some desired molecules, such as H₂O₂ and glucose,is also reduced.

One method, of manipulating the hydrophobe-hydrophile balance of theinterference domain, is to select the appropriate percentages of acetylgroups (relatively more hydrophilic than butyl groups), butyl groups(relatively more hydrophobic than acetyl groups) and hydroxyl groups ofthe cellulose acetate butyrate used to form the interference domain 44.For example, increasing the percentage of acetate groups on thecellulose acetate butyrate will make the cellulose acetate butyrate morehydrophilic. In another example, increasing the percentage of butylgroups on the cellulose acetate butyrate will make the cellulose acetatebutyrate more hydrophobic. In yet another example, increasing thepercentage of hydroxyl groups will increase the hydrophilicity of thecellulose acetate butyrate. Accordingly, the selection of a celluloseacetate butyrate that is more or less hydrophilic (or more or lesshydrophobic) can modulate the over-all hydrophilicity of the celluloseacetate/cellulose acetate butyrate blend. In one exemplary embodiment,an interference domain can be configured to be relatively morehydrophobic (and therefore block interferants more strongly) by reducingthe percentage of acetyl or hydroxyl groups or by increasing thepercentage of butyl groups on the cellulose acetate butyrate used in thecasting solution (while maintaining the relative ratio of celluloseacetate to cellulose acetate butyrate).

In some alternative embodiments, the interference domain is formed of ablend of cellulosic derivatives, wherein the hydrophilic and hydrophobiccomponents of the interference domain are balanced, such that theglucose sensitivity is from about 1 pA/mg/dL to about 100 pA/mg/dL, andat least one interferent is sufficiently blocked from passage throughthe interference domain such that the equivalent glucose signal responseof the at least one interferent is less than about 60 mg/dL. In apreferred embodiment, the glucose sensitivity is from about 5 pA/mg/dLto about 25 pA/mg/dL. In a more preferred embodiments, the glucosesensitivity is from about 5 pA/mg/dL to about 25 pA/mg/dL and theequivalent glucose signal response of the at least one interferent isless than about 40 mg/dL. In a still more preferred embodiments, theglucose sensitivity is from about 5 pA/mg/dL to about 25 pA/mg/dL andthe equivalent glucose signal response of the at least one interferentis less than about 30 mg/dL. In some embodiments, the balance betweenhydrophilic and hydrophobic components of the interference domain can beachieved by adjusting the amounts of hydrophilic and hydrophobiccomponents, relative to each other, as well as adjusting the hydrophilicand hydrophobic groups (e.g., acetyl, butyryl, propionyl, methoxy,ethoxy, propoxy, hydroxyl, carboxymethyl, and/or carboxyethyl groups) ofthe components themselves (e.g., cellulosic derivatives, such as but notlimited to cellulose acetate and cellulose acetate butyrate).

In some alternative embodiments, additional polymers, such as Nafion®,can be used in combination with cellulosic derivatives to provideequivalent and/or enhanced function of the interference domain 44. Asone example, a layer of a 5 wt. % Nafion® casting solution was appliedover a previously applied (e.g., and cured) layer of 8 wt. % celluloseacetate, e.g., by dip coating at least one layer of cellulose acetateand subsequently dip coating at least one layer Nafion® onto aneedle-type sensor such as described with reference to the preferredembodiments. Any number of coatings or layers formed in any order may besuitable for forming the interference domain of the preferredembodiments.

In some alternative embodiments, more than one cellulosic derivative canbe used to form the interference domain 44 of the preferred embodiments.In general, the formation of the interference domain on a surfaceutilizes a solvent or solvent system, in order to solvate the cellulosicderivative(s) (or other polymer) prior to film formation thereon. Inpreferred embodiments, acetone and ethanol are used as solvents forcellulose acetate; however one skilled in the art appreciates thenumerous solvents that are suitable for use with cellulosic derivatives(and other polymers). Additionally, one skilled in the art appreciatesthat the preferred relative amounts of solvent can be dependent upon thecellulosic derivative (or other polymer) used, its molecular weight, itsmethod of deposition, its desired thickness, and the like. However, apercent solute of from about 1 wt. % to about 25 wt. % is preferablyused to form the interference domain solution so as to yield aninterference domain having the desired properties. The cellulosicderivative (or other polymer) used, its molecular weight, method ofdeposition, and desired thickness can be adjusted, depending upon one ormore other of the parameters, and can be varied accordingly as isappreciated by one skilled in the art.

In some alternative embodiments, other polymer types that can beutilized for the interference domain 44 including polyurethanes,polymers having pendant ionic groups, and polymers having controlledpore size, for example. In one such alternative embodiment, theinterference domain includes a thin, hydrophobic membrane that isnon-swellable and restricts diffusion of high molecular weight species.The interference domain is permeable to relatively low molecular weightsubstances, such as hydrogen peroxide, but restricts the passage ofhigher molecular weight substances, including glucose and ascorbic acid.Other systems and methods for reducing or eliminating interferencespecies that can be applied to the membrane system of the preferredembodiments are described in U.S. Pat. No. 7,074,307, U.S. PatentPublication No. US-2005-0176136-A1, U.S. Pat. No. 7,081,195, and U.S.Patent Publication No. US-2005-0143635-A1. In some alternativeembodiments, a distinct interference domain is not included.

In some embodiments, the interference domain 44 is deposited eitherdirectly onto the electroactive surfaces of the sensor or onto thedistal surface of the electrode domain, for a domain thickness of fromabout 0.05 microns or less to about 20 microns or more, more preferablyfrom about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1,1.5, 2, 2.5, 3, or 3.5 microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and more preferably stillfrom about 1, 1.5 or 2 microns to about 2.5 or 3 microns. Thickermembranes can also be desirable in certain embodiments, but thinnermembranes are generally preferred because they have a lower impact onthe rate of diffusion of hydrogen peroxide from the enzyme membrane tothe electrodes. In some embodiments, the interference domain can bedeposited either more proximal or more distal than the electrode domain,relative to the electroactive surfaces, depending upon the interferencedomain composition and membrane system configuration.

In general, the membrane systems of the preferred embodiments can beformed and/or deposited on the exposed electroactive surfaces (e.g., oneor more of the working and reference electrodes) using known thin filmtechniques (for example, casting, spray coating, drawing down,electro-depositing, dip coating, and the like), however casting or otherknown application techniques can also be utilized. Preferably, theinterference domain is deposited by spray or dip coating. In oneexemplary embodiment of a needle-type (transcutaneous) sensor such asdescribed herein, the interference domain is formed by dip coating thesensor into an interference domain solution using an insertion rate offrom about 0.5 inch/min to about 60 inches/min, preferably 1 inch/min, adwell time of from about 0 minute to about 2 minutes, preferably about 1minute, and a withdrawal rate of from about 0.5 inch/minute to about 60inches/minute, preferably about 1 inch/minute, and curing (drying) thedomain from about 1 minute to about 30 minutes, preferably from about 3minutes to about 15 minutes (and can be accomplished at room temperatureor under vacuum (e.g., 20 to 30 mmHg)). In one exemplary embodimentincluding cellulose acetate butyrate interference domain, a 3 minutecure (i.e., dry) time is preferred between each layer applied. Inanother exemplary embodiment employing a cellulose acetate interferencedomain, a 15 minute cure (i.e., dry) time is preferred between eachlayer applied.

In some embodiments, the dip process can be repeated at least one timeand up to 10 times or more. In other embodiments, only one dip ispreferred. The preferred number of repeated dip processes depends uponthe cellulosic derivative(s) used, their concentration, conditionsduring deposition (e.g., dipping) and the desired thickness (e.g.,sufficient thickness to provide functional blocking of certaininterferents), and the like. In some embodiments, 1 to 3 microns may bepreferred for the interference domain thickness; however, values outsideof these can be acceptable or even desirable in certain embodiments, forexample, depending upon viscosity and surface tension, as is appreciatedby one skilled in the art. In one exemplary embodiment, an interferencedomain is formed from three layers of cellulose acetate butyrate. Inanother exemplary embodiment, an interference domain is formed from 10layers of cellulose acetate. In another embodiment, an interferencedomain is formed from 1 layer of a blend of cellulose acetate andcellulose acetate butyrate. In alternative embodiments, the interferencedomain can be formed using any known method and combination of celluloseacetate and cellulose acetate butyrate, as will be appreciated by oneskilled in the art.

In some embodiments, the electroactive surface can be cleaned prior toapplication of the interference domain 44. In some embodiments, theinterference domain of the preferred embodiments can be useful as abioprotective or biocompatible domain, namely, a domain that interfaceswith host tissue when implanted in an animal (e.g., a human) due to itsstability and biocompatibility.

In some embodiments, the interference domain is formed of asilicone-hydrophilic/hydrophobic polymer blend, such as but not limitedto a silicone-Pluronic polymer blend, such as described in the sectionentitled “Silicone/Hydrophilic Polymer Blend Materials.”

Enzyme Domain

In preferred embodiments, the membrane system further includes an enzymedomain 46 disposed more distally from the electroactive surfaces thanthe interference domain; however other configurations can be desirable(FIGS. 2E-2F). In the preferred embodiments, the enzyme domain providesan enzyme to catalyze the reaction of the analyte and its co-reactant,as described in more detail below. In the preferred embodiments of aglucose sensor, the enzyme domain includes glucose oxidase; howeverother oxidases, for example, galactose oxidase or uricase oxidase, canalso be used.

For an enzyme-based electrochemical glucose sensor to perform well, thesensor's response is preferably limited by neither enzyme activity norco-reactant concentration. Because enzymes, including glucose oxidase(GOX), are subject to deactivation as a function of time even in ambientconditions, this behavior is compensated for in forming the enzymedomain. Preferably, the enzyme domain is constructed of aqueousdispersions of colloidal polyurethane polymers including the enzyme.However, in alternative embodiments the enzyme domain is constructedfrom an oxygen enhancing material, for example, silicone, orfluorocarbon, in order to provide a supply of excess oxygen duringtransient ischemia. Preferably, the enzyme is immobilized within thedomain. See, e.g., U.S. Patent Publication No. US-2005-0054909-A1.

In preferred embodiments, the enzyme domain 46 is deposited onto theinterference domain 44 for a domain thickness of from about 0.05 micronor less to about 20 microns or more, more preferably from about 0.05,0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or3.5 microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, or 19.5 microns, and more preferably still from about 2, 2.5 or3 microns to about 3.5, 4, 4.5, or 5 microns. However in someembodiments, the enzyme domain can be deposited directly onto theelectroactive surfaces. Preferably, the enzyme domain is deposited byspray or dip coating. In one embodiment of needle-type (transcutaneous)sensor such as described herein, the enzyme domain is formed by dipcoating the interference domain coated sensor into an enzyme domainsolution and curing the domain for from about 15 minutes to about 30minutes at a temperature of from about 40° C. to about 55° C. (and canbe accomplished under vacuum (e.g., 20 to 30 mmHg)). In embodimentswherein dip coating is used to deposit the enzyme domain at roomtemperature, a preferred insertion rate of from about 0.25 inches perminute to about 3 inches per minute, with a preferred dwell time of fromabout 0.5 minutes to about 2 minutes, and a preferred withdrawal rate offrom about 0.25 inch per minute to about 2 inches per minute provides afunctional coating. However, values outside of those set forth above canbe acceptable or even desirable in certain embodiments, for example,depending upon viscosity and surface tension, as is appreciated by oneskilled in the art. In one embodiment, the enzyme domain is formed bydip coating two times (namely, forming two layers) in an enzyme domainsolution and curing at 50° C. under vacuum for 20 minutes. However, insome embodiments, the enzyme domain can be formed by dip coating and/orspray coating one or more layers at a predetermined concentration of thecoating solution, insertion rate, dwell time, withdrawal rate, and/ordesired thickness.

FIG. 3A is a cross-sectional view of a membrane system, in oneembodiment, illustrating the diffusion distance D₁ between H₂O₂generated in the enzyme domain and the electroactive surface of theelectrode 38. Generally, when H₂O₂ 310 is generated by the metabolism ofglucose by GOX (in the enzyme domain 46), the generated H₂O₂ can diffusein all directions (e.g., from the location within the enzyme domainwhere the H₂O₂ was generated). A portion of the generated H₂O₂ diffusesa distance D₁ to the electroactive surface and generates a signalrelated to the analyte (e.g., FIG. 3A).

FIG. 3B is a cross-sectional view of a membrane system, in anotherembodiment, illustrating the diffusion distance D₂ between H₂O₂generated in the enzyme domain and the electroactive surface. In thisembodiment, the distance D₂ between the location of H₂O₂ generation andthe electroactive surface is reduced (relative to D₁). Thus more of theH₂O₂ will reach the electroactive surface and be detected in theembodiment of FIG. 3B relative to the embodiment of FIG. 3A.

FIG. 3C is a cross-sectional view of a membrane system, in yet anotherembodiment, illustrating the diffusion distance D₃ between H₂O₂generated in the enzyme domain and the electroactive surface. Namely, inthe embodiment shown in FIG. 3C, the distance D₃ between the location ofH₂O₂ generation and the electroactive surface is reduced (relative to D₁and D₂). Thus even more of the H₂O₂ (relative to the embodiments ofFIGS. 3A and 3B) will contact the electroactive surface and be detectedin the embodiment of FIG. 3C. Accordingly, in preferred embodiments, thesystem is configured such that the analyte component of the signal is atleast 80% of the total signal, at least in part, due to a preferred H₂O₂diffusion distance. In some embodiments, the preferred diffusiondistance is achieved by including GOX in the layer adjacent to theelectrode (i.e., in an H₂O₂ diffusion-based sensors). In someembodiments, the preferred diffusion distance is less than about 20 μm.In some preferred embodiments, the preferred diffusion distance is lessthan about 10 μm. In some preferred embodiments, the preferred diffusiondistance is less than about 5 μm. In still other preferred embodiments,the preferred diffusion distance is less than about 1 μm. In preferredembodiments, the analyte component is at least 80% of the total signalfor a period of at least one day.

In some embodiments, the enzyme domain 46 is located adjacent to theelectroactive surfaces (e.g., by eliminating or combining the functionsof the electrode and/or interference domains). In some embodiments, theenzyme (e.g., GOX) can be contained within the electrode domain, forexample, using a coupling agent. Suitable coupling agents include butare not limited to disulfosuccinimidyl tartarate (sulfo-DST),bis(sulfosuccinimidyl) suberate (BS3), ethylene glycolbis(sulfosuccinimidyl succinate (Sulfo-EGS),3,3′-Dithiobis(sulfosuccinimidyl propionate) (DTS SP),N,N′1,3-phenylenedimaleimide (mPDM), N,N′-1,2-phenylenedimaleimide(oPDM), N,N′-1,4-phenylenedimaleimide (pPDM),N,N′-(methylene-4-1-phenylene)bismaleimide (BM),naphthalene-1,5-dimaleimide (NDM), bismaleimidoethane (BMOE),1,4-bismaleimidobutane (BMB), 1,4-bis-maleimidyl-2,3-dihydroxybutane(BMDB), dithio-bis-maleimdoethane (DTME), 1,6-bismaleimidohexane (BMH),1,8-bismaleimidotriethyleneglycol (BM[PEO]3),1,11-bis-maleimidotetraethylenegly col (BM[PEO]4), dimethyl adipimidate(DMA), dimethyl pimelimidiate (DMP), dimethyl suberimidate (DMS),dimethyl 3,3′-dithiobis-propionimidate (DTBP), disuccimimidyl tartarate(DST), disuccinimidyl glutarate (DSG), dithiobis(succinimidylpropionate)(DSP), disuccinimidyl suberate (DSS),bis(2-[succinimidooxycarbonyloxy]ethyl)sulfone (BSOCOES), ethyleneglycolbis-(succinimidylsuccinate) (EGS), 1,5-difluro-2,4dinitrobenzene(DFDNB), 4,4′-difluoro3,3′-dinitrodiphenylsulfone (DFDNPS),dibromobimane (bBBr) and the like. In some embodiments, the enzyme(e.g., GOX) can be absorbed to the electroactive surface (usingtechniques known in the art), such as by dipping the electrode into anenzyme solution and allowing the electrode to dry, followed byapplication of at least one membrane domain. In still other embodiments,the enzyme can be mixed with the electrode domain material (e.g., a PVPor other hydrophilic polymer) and applied to the electroactive surfaceto form the electrode domain. Additionally, the thickness of the enzymedomain, itself, can be adjusted to increase the analyte component of thesignal. In some embodiments, the enzyme domain has a thickness of about10 μm or less. In some preferred embodiments, the enzyme domain has athickness of about 5 μm or less. In a more preferred embodiment, theenzyme domain has a thickness of about 2 μm or less.

In some embodiments, the enzyme domain is configured to adjust H₂O₂utilization and/or production, such as by including a coenzyme in theenzyme domain, or in membrane domains more proximal to the electroactivesurface than the enzyme domain. In some circumstances, coenzymes canstabilize enzyme reactions products (e.g., H₂O₂ from the metabolizationof glucose by GOX) and/or increase the enzyme's reaction efficiency. Forexample, NADPH co-localized with other enzyme systems dramaticallyincreases the enzyme's effectiveness. Suitable coenzymes include but arenot limited to superoxide dismutase (SOD), hydrogenases, reductases,oxidases, peroxidases, flavoenzymes and NADPH. For example, the reactionproduct (e.g., H₂O₂) can be stabilized by compounds such as SOD, whicheliminate more reactive oxygen radical species and can enhance the lifeof the reaction product (H₂O₂). Stabilization of the reaction productand/or adjustment of the enzyme reaction rate can produce acorresponding increase in the analyte signal. Accordingly, in someembodiments, the sensor is configured such that (after complete sensorbreak-in) the analyte signal is at least 80% of the total signal for aperiod of at least one day. In some preferred embodiments, the analytesignal is at least 90% of the total signal for a period of at least twodays.

In some embodiments, an enzymatic, electrochemical analyte sensorincludes at least one working electrode (that includes an electroactivesurface) and a membrane system (including an enzyme domain) configuredsuch that the enzyme domain is substantially adjacent to theelectroactive surface. Additionally, the sensor is configured to detectH₂O₂ that diffuses from its location of synthesis (e.g., within theenzyme domain) to the electroactive surface (after sensor break-in iscomplete), such that the analyte component is at least 80% of the totalsignal, for a period of at least one day. In preferred embodiments, thesensor is configured such that the non-constant noise component does notsubstantially contribute to the total signal. For example, in somepreferred embodiments, the non-constant noise component is less than 20%of the total signal over period of one or more days.

Resistance Domain

In preferred embodiments, the membrane system 32 includes a resistancedomain 48 disposed more distal from the electroactive surfaces than theenzyme domain 46 (e.g., FIGS. 2E-2F). Although the following descriptionis directed to a resistance domain for a glucose sensor, the resistancedomain can be modified for other analytes and co-reactants as well.

There exists a molar excess of glucose relative to the amount of oxygenin blood; that is, for every free oxygen molecule in extracellularfluid, there are typically more than 100 glucose molecules present (seeUpdike et al., Diabetes Care 5:207-21(1982)). However, an immobilizedenzyme-based glucose sensor employing oxygen as co-reactant ispreferably supplied with oxygen in non-rate-limiting excess in order forthe sensor to respond linearly to changes in glucose concentration,while not responding to changes in oxygen concentration. Specifically,when a glucose-monitoring reaction is oxygen limited, linearity is notachieved above minimal concentrations of glucose. Without asemipermeable membrane situated over the enzyme domain to control theflux of glucose and oxygen, a linear response to glucose levels can beobtained only for glucose concentrations of up to about 40 mg/dL.However, in a clinical setting, a linear response to glucose levels isdesirable up to at least about 400 mg/dL.

The resistance domain 48 includes a semipermeable membrane that controlsthe flux of oxygen and glucose to the underlying enzyme domain 46,preferably rendering oxygen in a non-rate-limiting excess. As a result,the upper limit of linearity of glucose measurement is extended to amuch higher value than that which is achieved without the resistancedomain. In one embodiment, the resistance domain exhibits an oxygen toglucose permeability ratio of from about 50:1 or less to about 400:1 ormore, preferably about 200:1. As a result, one-dimensional reactantdiffusion is adequate to provide excess oxygen at all reasonable glucoseand oxygen concentrations found in the subcutaneous matrix (See Rhodeset al., Anal. Chem., 66:1520-1529 (1994)).

In alternative embodiments, a lower ratio of oxygen-to-glucose can besufficient to provide excess oxygen by using a high oxygen solubilitydomain (for example, a silicone or fluorocarbon-based material ordomain) to enhance the supply/transport of oxygen to the enzyme domain.If more oxygen is supplied to the enzyme, then more glucose can also besupplied to the enzyme without creating an oxygen rate-limiting excess.In alternative embodiments, the resistance domain is formed from asilicone composition, such as is described in U.S. Patent PublicationNo. US-2005-0090607-A1.

Polyurethane Polymer Materials

In a preferred embodiment, the resistance domain includes a polyurethanemembrane with both hydrophilic and hydrophobic regions to control thediffusion of glucose and oxygen to an analyte sensor, the membrane beingfabricated easily and reproducibly from commercially availablematerials. A suitable hydrophobic polymer component is a polyurethane,or polyetherurethaneurea. Polyurethane is a polymer produced by thecondensation reaction of a diisocyanate and a difunctionalhydroxyl-containing material. A polyurethaneurea is a polymer producedby the condensation reaction of a diisocyanate and a difunctionalamine-containing material. Preferred diisocyanates include aliphaticdiisocyanates containing from about 4 to about 8 methylene units.Diisocyanates containing cycloaliphatic moieties can also be useful inthe preparation of the polymer and copolymer components of the membranesof preferred embodiments. The material that forms the basis of thehydrophobic matrix of the resistance domain can be any of those known inthe art as appropriate for use as membranes in sensor devices and ashaving sufficient permeability to allow relevant compounds to passthrough it, for example, to allow an oxygen molecule to pass through themembrane from the sample under examination in order to reach the activeenzyme or electrochemical electrodes. Examples of materials which can beused to make non-polyurethane type membranes include vinyl polymers,polyethers, polyesters, polyamides, inorganic polymers such aspolysiloxanes and polycarbosiloxanes, natural polymers such ascellulosic and protein based materials, and mixtures or combinationsthereof.

In a preferred embodiment, the hydrophilic polymer component ispolyethylene oxide. For example, one useful hydrophobic-hydrophiliccopolymer component is a polyurethane polymer that includes about 5%hydrophilic polyethylene oxide. The polyethylene oxide portions of thecopolymer are thermodynamically driven to separate from the hydrophobicportions of the copolymer and the hydrophobic polymer component. The 5%polyethylene oxide-based soft segment portion of the copolymer used toform the final blend affects the water pick-up and subsequent glucosepermeability of the membrane.

In some embodiments, alternative polyurethanes, which include urethanegroups and the polyurethane ureas (which also include urea groups), canbe used to configure the resistance domain to regulate the flux of theanalyte (e.g., glucose) therethrough, and preferably to increase thesignal-to-noise ratio. For example, the polyurethanes and thepolyurethane ureas selected to form the resistance domain can be basedon poly(oxyalkylene) glycols including poly(oxyethylene) glycol. Inaccordance with conventional usage, both types of polymers will bereferred to herein as polyurethanes. Membranes of polyurethanes based onpoly(oxyalkylene) glycol display no predictable relationship betweenmolecular weight and permeability. The unique separation observed withthe present membranes may be explained on the basis ofsubstance-membrane or solute-membrane interactions which tend to affectthe partitioning is not due only to the hydrophilic poly(oxyalkylene)glycol or “soft” segment, but the hydrophobic or “hard” segment of theblock copolymer also contributes to the overall selectivity. Thus, bychanging the structure of the hydrophobic segment of the block copolymerand/or increasing or decreasing the molecular weight of thepoly(oxyalkylene) glycol, the selectivity of the membrane system can bemodified. In the membrane system of some embodiments, for example, theuse of two different membranes of block copolyether urethanes based onpoly(oxyalkylene) glycol produces the desired selectivity for glucoseand hydrogen peroxide. Additional description of polyurethane resistancedomains can be found in PCT International Publication No. WO1992/013271.

In preferred embodiments, the resistance domain is deposited onto theenzyme domain to yield a domain thickness of from about 0.05 microns orless to about 20 microns or more, more preferably from about 0.05, 0.1,0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, or 19.5 microns, and more preferably still from about 2, 2.5 or 3microns to about 3.5, 4, 4.5, or 5 microns. Preferably, the resistancedomain is deposited onto the enzyme domain by vapor deposition, spraycoating, or dip coating. In one preferred embodiment, spray coating isthe preferred deposition technique. The spraying process atomizes andmists the solution, and therefore most or all of the solvent isevaporated prior to the coating material settling on the underlyingdomain, thereby minimizing contact of the solvent with the enzyme.

In a preferred embodiment, the resistance domain is deposited on theenzyme domain by spray coating a solution of from about 1 wt. % to about5 wt. % polymer and from about 95 wt. % to about 99 wt. % solvent. Inspraying a solution of resistance domain material, including a solvent,onto the enzyme domain, it is desirable to mitigate or substantiallyreduce any contact with enzyme of any solvent in the spray solution thatcan deactivate the underlying enzyme of the enzyme domain.Tetrahydrofuran (THF) is one solvent that minimally or negligiblyaffects the enzyme of the enzyme domain upon spraying. Other solventscan also be suitable for use, as is appreciated by one skilled in theart.

Silicone/Hydrophilic Polymer Blend Materials

It is believed that incorporation of a silicone-hydrophilic polymerblend into the membrane system can render the signal-to-noise ratio ofthe sensor substantially unaffected by non-constant noise bysubstantially reducing and/or eliminating noise, such as bysubstantially blocking and/or slowing (e.g., reducing the diffusionrate) the passage of an interferent therethrough. In preferredembodiments, a sensor having one or more working electrodes includes amembrane system 34 wherein the resistance domain 48 includes a blend ofa silicone polymer with a hydrophilic polymer configured to reducenoise-causing species, such as non-constant noise-causing species. Insome embodiments, the membrane domains/layers include a blend of asilicone polymer with a hydrophilic polymer configured to reducenoise-causing species. In some preferred embodiments, the sensorincludes a silicone-hydrophilic polymer blend membrane domain and/orlayer (e.g., an interference domain) that has a micellar jacketstructure (described elsewhere herein). While not wishing to be bound bytheory, it is believed that membrane domains that include asilicone-hydrophilic polymer blend can reduce noise by blocking and/orsuppressing passage of at least one interfering species into themembrane system, while at the same time allowing for and/or promotingthe transport of the analyte (e.g., glucose or other such water-solublemolecules, such as drugs).

By “hydrophilic polymer,” it is meant that the polymer has an affinityfor water, due to the presence of one or more hydrophilic substituents,and generally is primarily soluble in water or has a tendency to absorbwater. In one example, the hydrophilic component of a hydrophilicpolymer promotes the movement of water and/or compounds in the water(e.g., by diffusion or other means) through a membrane formed of thehydrophilic polymer, such as by lowering the thermodynamic barrier tomovement of compounds in the water into the membrane.

In some embodiments, hydrophilic polymers includehydrophilic-hydrophobic polymers. Generally, the terms“hydrophilic-hydrophobic” and “hydrophobic-hydrophilic” are usedinterchangeably herein (are not meant to imply that either thehydrophilic or the hydrophobic substituents are the major component ofthe polymer) and refer to the property of having both hydrophilic andhydrophobic substituents and/or characteristics in a single molecule,such as, for example, a polymer.

The hydrophilic and hydrophobic substituents of a polymer can affect thepolymer's behavior in certain circumstances, such as but not limited tosilicone/hydrophilic-hydrophobic blend materials and micellar jackets,which are discussed elsewhere herein. Using PEO—PPO-PEO as an exemplarypolymer, the polymer's major component (PEO) is hydrophilic and canprovide an overall hydrophilic character to the molecule (e.g., themolecule generally behaves in a hydrophilic manner). However, thehydrophobic component (PPO) of the polymer makes it possible for thepolymer to have some hydrophobic character (e.g., for portions of themolecule to behave in the manner of a hydrophobic molecule), in somesituations. In some circumstances, such as formation of micellar jacketsin a silicone/hydrophilic-hydrophobic blend material, the polymerself-organizes, relative to the silicone (e.g., silicone globule(s))such that the hydrophobic PPO is adjacent to the silicone (which ishydrophobic) and the two PEO groups project away from the silicone(e.g., due to thermodynamic forces). Depending upon the circumstance(e.g., the polymer selected), variations of the micellar jacketstructure described above (e.g., opposite orientations) are possible.For example, it is believed that in a mixture of PPO-PEO-PPO andsilicone, the PPO groups self-orient toward the silicone and the PEOcenter is oriented away from the silicone.

In one embodiment, the hydrophilic polymer has a molecular weight of atleast about 1000 g/mol, 5,000 g/mol, 8,000 g/mol, 10,000 g/mol, or15,000 g/mol or more. In one embodiment, the hydrophilic polymercomprises both a hydrophilic domain and a partially hydrophobic domain(e.g., a copolymer, also referred to herein as a hydrophobic-hydrophilicpolymer). The hydrophobic domain(s) facilitate the blending of thehydrophilic polymer with the hydrophobic silicone polymer, such as butnot limited to formation of micellar jackets within and/or around thesilicone. In one embodiment, the hydrophobic domain is itself a polymer(i.e., a polymeric hydrophobic domain). For example, in one embodiment,the hydrophobic domain is not a simple molecular head group but israther polymeric. In various embodiments, the molecular weight of anycovalently continuous hydrophobic domain within the hydrophilic polymeris at least about 500 g/mol, 700 g/mol, 1000 g/mol, 2000 g/mol, 5000g/mol, or 8,000 g/mol or more. In various embodiments, the molecularweight of any covalently continuous hydrophilic domain within thehydrophilic polymer is at least about 500 g/mol, 700 g/mol, 1000 g/mol,2000 g/mol, 5000 g/mol, or 8,000 g/mol or more.

In some embodiments, within a particular layer, the ratio of thesilicone polymer to hydrophilic polymer is selected to provide an amountof oxygen and water-soluble molecule solubility such that oxygen andwater-soluble molecule transport through a domain is adjusted accordingto the desired function of that particular layer. Furthermore, in someembodiments, the ratio of silicone polymer to hydrophilic polymer, aswell as the polymeric compositions, is selected such that a layerconstructed from the material has interference characteristics thatinhibit transport of one or more interfering species through the layer.Some known interfering species for a glucose sensor include, but are notlimited to, acetaminophen, ascorbic acid, bilirubin, cholesterol,creatinine, dopamine, ephedrine, ibuprofen, L-dopa, methyldopa,salicylate, tetracycline, tolazamide, tolbutamide, triglycerides, anduric acid. Accordingly, in some embodiments, a siliconepolymer/hydrophilic polymer layer as disclosed herein is less permeableto one or more of these interfering species than to the analyte, e.g.,glucose.

In some of these embodiments, the ratio of silicone polymer tohydrophilic polymer (in the layers incorporating the blends) variesaccording to the desired functionality of each layer. The relativeamounts of silicone polymer and hydrophilic polymer described below arebased on the respective amounts found in the cured polymeric blend. Uponintroduction into an aqueous environment, some of the polymericcomponents may leach out, thereby changing the relative amounts ofsilicone polymer and hydrophilic polymer. For example, substantialamounts of the portions of the hydrophilic polymer that are notcross-linked may leach out, for example, depending on the hydrophilicpolymer's molecular weight and how tortuous it the diffusion path out ofthe membrane.

In some embodiments, the silicone and hydrophilic polymers form asubstantial blend. Namely, the amount of any cross-linking between thesilicone polymer and the hydrophilic polymer is substantially limited.In various embodiments, at least about 75%, 85%, 95%, or 99% or more ofthe silicone polymer is not covalently linked to the hydrophilicpolymer. In some embodiments, the silicone polymer and the hydrophilicpolymer do not cross-link at all unless a cross-linking agent is used(e.g., such as described below). Similarly, in some embodiments, theamount of any entanglement (e.g., blending on a molecular level) betweenthe silicone polymer and the hydrophilic polymer is substantiallylimited. In one embodiment, the silicone polymer and hydrophilicpolymers form microdomains. For example, in one embodiment, the siliconepolymer forms micellar jacket structures surrounded by a network ofhydrophilic polymer.

The silicone polymer for use in the silicone/hydrophilic polymer blendmay be any suitable silicone polymer. In some embodiments, the siliconepolymer is a liquid silicone rubber that may be vulcanized using ametal-(e.g., platinum), peroxide-, heat-, ultraviolet-, or otherradiation-catalyzed process. In some embodiments, the silicone polymeris a dimethyl- and methylhydrogen-siloxane copolymer. In someembodiments, the copolymer has vinyl substituents. In some embodiments,commercially available silicone polymers may be used. For example,commercially available silicone polymer precursor compositions may beused to prepare the blends, such as described below. In one embodiment,MED-4840 available from NUSIL® Technology LLC is used as a precursor tothe silicone polymer used in the blend. MED-4840 consists of a 2-partsilicone elastomer precursor including vinyl-functionalized dimethyl-and methylhydrogen-siloxane copolymers, amorphous silica, a platinumcatalyst, a crosslinker, and an inhibitor. The two components may bemixed together and heated to initiate vulcanization, thereby forming anelastomeric solid material. Other suitable silicone polymer precursorsystems include, but are not limited to, MED-2174 peroxide-cured liquidsilicone rubber available from NUSIL® Technology LLC, SILASTIC®MDX4-4210 platinum-cured biomedical grade elastomer available from DOWCORNING®, and Implant Grade Liquid Silicone Polymer (durometers 10-50)available from Applied Silicone Corporation.

The hydrophilic polymer for use in the blend may be any suitablehydrophilic polymer, including but not limited to components such aspolyvinylpyrrolidone (PVP), polyhydroxyethyl methacrylate,polyvinylalcohol, polyacrylic acid, polyethers such as polyethyleneglycol or polypropylene oxide, and copolymers thereof, including, forexample, di-block, tri-block, alternating, random, comb, star,dendritic, and graft copolymers (block copolymers are discussed in U.S.Pat. Nos. 4,803,243 and 4,686,044, which are incorporated herein byreference). In one embodiment, the hydrophilic polymer is a copolymer ofpoly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO). Suitablesuch polymers include, but are not limited to, PEO-PPO diblockcopolymers, PPO-PEO-PPO triblock copolymers, PEO—PPO-PEO triblockcopolymers, alternating block copolymers of PEO-PPO, random copolymersof ethylene oxide and propylene oxide, and blends thereof. In someembodiments, the copolymers may be optionally substituted with hydroxysubstituents. Commercially available examples of PEO and PPO copolymersinclude the PLURONIC® brand of polymers available from BASF®. SomePLURONIC® polymers are triblock copolymers of poly(ethyleneoxide)-poly(propylene oxide)-poly(ethylene oxide) having the generalmolecular structure:

HO—(CH₂CH₂O)_(x)—(CH₂CH₂CH₂O)_(y)—(CH₂CH₂O)_(x)—OH

wherein the repeat units x and y differ amongst various PLURONIC®products. The poly(ethylene oxide) blocks act as a hydrophilic domainallowing the dissolution of aqueous agents in the polymer. Thepoly(propylene oxide) block acts as a hydrophobic domain facilitatingthe blending of the PLURONIC® polymer with a silicone polymer. In oneembodiment, PLURONIC® F-127 is used having x of approximately 100 and yof approximately 65. The molecular weight of PLURONIC® F-127 isapproximately 12,600 g/mol as reported by the manufacture. OtherPLURONIC® polymers include PPO-PEO-PPO triblock copolymers (e.g.,PLURONIC® R products) and PEO-PDMS-PEO triblock copolymers (e.g.,PEO-polydimethylsiloxane-PEO, SILSURF® from BASF, USA) Other suitablecommercial polymers include, but are not limited to, SYNPERONICS®products available from UNIQEMA®.

The polyether structure of PLURONIC® polymers is relatively inert.Accordingly, without being bound by any particular theory, it isbelieved that the PLURONIC® polymers do not substantially react with thecomponents in MED-4840 or other silicone polymer precursors.

Those of skill in the art will appreciate that other copolymers havinghydrophilic and hydrophobic domains may be used. For example, in onealternative embodiment, a triblock copolymer having the structurehydrophobic-hydrophilic-hydrophobic may be used. In another alternativeembodiment, a diblock copolymer having the structurehydrophilic-hydrophobic is used. Additional devices, methods andcompositions are described in U.S. Patent Publication No.US-2006-0270923-A1 and U.S. patent application Ser. No. 11/404,417 filedon Apr. 14, 2006.

Layers and/or domains that include a silicone polymer-hydrophilicpolymer blend can be made using any of the methods of forming polymerblends known in the art. In one embodiment, a silicone polymer precursor(e.g., MED-4840) is mixed with a solution of a hydrophilic polymer(e.g., PLURONIC® F-127 dissolved in a suitable solvent such as acetone,ethyl alcohol, xylene or 2-butanone). The mixture may then be drawn intoa film or applied in a multi-layer membrane structure using any methodknown in the art (e.g., spraying, painting, dip coating, vapordepositing, molding, 3-D printing, lithographic techniques (e.g.,photolithograph), micro- and nano-pipetting printing techniques, etc.).The mixture may then be cured under high temperature (e.g., 50° C. to150° C.). Other suitable curing methods include ultraviolet or gammaradiation, for example. During curing, the silicone polymer precursorwill vulcanize and the solvent will evaporate. In one embodiment, afterthe mixture is drawn into a film, another preformed layer of themembrane system is placed on the film. Curing of the film then providesbonding between the film and the other preformed layer. In oneembodiment, the preformed layer is the cell disruptive layer. In oneembodiment, the cell disruptive domain comprises a preformed poroussilicone membrane. In other embodiments, the cell disruptive domain isalso formed from a silicone polymer/hydrophilic polymer blend. In someembodiments, multiple films are applied on top of the preformed layer.Each film may posses a finite interface with adjacent films or maytogether form a physically continuous structure having a gradient inchemical composition.

Some amount of cross-linking agent may also be included in the mixtureto induce cross-linking between hydrophilic polymer molecules. Forexample, when using a PLURONIC® polymer, a cross-linking system thatreacts with pendant or terminal hydroxy groups or methylene, ethylene,or propylene hydrogen atoms may be used to induce cross linking.Non-limiting examples of suitable cross-linking agents include ethyleneglycol diglycidyl ether (EGDE), poly(ethylene glycol) diglycidyl ether(PEGDE), or dicumyl peroxide (DCP). While not being bound by anyparticular theory, at low concentrations, these cross-linking agents arebelieved to react primarily with the PLURONIC® polymer with some amountpossibly inducing cross-linking in the silicone polymer or between thePLURONIC® polymer and the silicone polymer. In one embodiment, enoughcross-linking agent is added such that the ratio of cross-linking agentmolecules to hydrophilic polymer molecules added when synthesizing theblend is from about 10 to about 30 (e.g., about 15 to about 20). In oneembodiment, from about 0.5% to about 15% w/w of cross-linking agent isadded relative to the total dry weights of cross-linking agent, siliconepolymer, and hydrophilic polymer added when blending the ingredients (inone example, from about 1% to about 10%). In one embodiment, from about5% to about 30% of the dry ingredient weight is the PLURONIC® polymer.

In some embodiments, other agents may be added to the mixture tofacilitate formation of the blend. For example, a small amount ofbutylhydroxy toluene (BHT) (e.g., about 0.01% w/w) or other suitableantioxidant may be mixed with a PLURONIC® to stabilize it.

In some alternative embodiments, precursors of both the silicone polymerand hydrophilic polymer may be mixed prior to curing such thatpolymerization of both the silicone polymer and the hydrophilic polymeroccur during curing. In another embodiment, already polymerized siliconepolymer is mixed with a hydrophilic polymer such that no significantpolymerization occurs during curing.

While not wishing to be bound by theory, it is believed that amicelle-like structure, referred to herein as a micellar jacketstructure, can be formed by combining certain hydrophobic polymers(e.g., silicone) with certain amphipathic polymers (e.g., hydrophilicpolymers such as PLURONIC® polymers), which, when substantially blended,create a mechanism by which glucose and other analytes are transportedat a limited rate. One example of a limited rate is diffusion of oxygenand glucose into the membrane at a ratio of 50:1 (50 oxygen moleculesfor every one glucose molecule). In a preferred embodiment, oxygen andglucose diffuse into the membrane at the limited rate of 100:1. In amore preferred embodiment, oxygen and glucose diffuse into the membraneat the limited rate of 200:1.

In a first mechanism of limited analyte transport, it is believed thatthe PLURONIC® hydrophilic and hydrophobic constituents can promoteself-organization of the PLURONIC® molecules, in conjunction with thesilicone, into micellar jackets. The micellar jackets provide acontiguous channel (e.g., a tortuous path) though the silicone, throughwhich the analyte travels. For example, at a first side of amembrane/domain, glucose dissolves into the hydrophilic component of themicellar jackets (e.g., within the membrane/domain) and diffuses throughthe hydrophilic portion of adjacent micellar jackets, to reach theopposite side of the membrane/domain.

In a second mechanism of limited analyte transport, it is believed thatmicellar jackets can provide a hydrophilic phase within the siliconemembrane/domain structure. There is an energetic barrier to diffusion ofthe analyte (e.g., glucose) into the silicone. However, an energetic,thermodynamic force (e.g., an analyte concentration gradient) drives theanalyte to pass across/through the membrane by “jumping” from onemicellar jacket to another. For example, a glucose concentrationgradient can provide the energy for a glucose molecule to pass into themembrane domain or layer (e.g., the cell impermeable domain formed of asubstantial blend of silicone and PLURONIC®), to the first micellarjacket, then to “jump” to the next micellar jacket, and so on, until themolecule reaches the opposite side of the membrane domain/layer.

In one exemplary embodiment, a silicone-hydrophilic polymer (e.g.,wherein the hydrophilic polymer is an amphipathic polymer, such as butnot limited to PLURONIC®) blend is believed to promote themacromolecular self-organization of micellar jackets that clothecolloidal silicone globules (e.g., silicone granules that form athree-dimensional contiguous macromolecular structure havingsilicone-to-silicone contacts between the silicone granules, coated withthe hydrophilic polymer), within the membrane domain. The hydrophilicgroups of the micellar jackets orient toward the silicone, with thehydrophobic portions of the polymer oriented away from the silicone coreof the structure. For example, in the case of silicone globules clothedwith PLURONIC® (PEO—PPO-PEO), it is believed that it isthermodynamically favorable for a PLURONIC® molecule to orient itselfsuch that the PPO “lies against” the silicone and the PEO to bends awayfrom the silicone, for example, in a U-like shape. Inverse micellarjackets are also possible, for example, inverted micellar jackets (e.g.,with the hydrophobic PPO facing outward toward the silicone and thehydrophilic PEO facing inward) within the silicone. Additionally, themicellar jackets may not be in direct, physical contact with each other,which would provide a thermodynamic barrier to molecules entering themembrane layer and traveling through/across the layer by energetically“jumping” from one micellar jacket to the next.

In addition to facilitating analyte passage through the membrane domain,it has been found that the micellar jacket structure blocks diffusion ofsmall, reactive oxygen and nitrogen interferents (e.g., H₂O₂, oxygenradicals, peroxynitrates, etc.) that can cause non-constant noise. Whilenot wishing to be bound by theory, it is believed that the micellarjacket structure sufficiently slows the diffusion of the reactive oxygenand nitrogen interferents such that these molecules self-annihilatebefore reaching the electroactive surface(s). In contrast, it isbelieved that large molecular weight interferents (e.g., acetaminophenand ascorbate) are sterically and/or thermodynamically blocked and/ortrapped by the micellar jackets, and thus do not reach the electroactivesurface(s). Accordingly, in preferred embodiments, the non-constantnoise produced by both small and large molecular weight interferents issubstantially attenuated, such that the non-constant noise component ofthe signal is less than 20% of the total signal for a period of at leastone day.

In one exemplary embodiment, an enzyme-based electrochemical sensor isconfigured to block non-constant, non-analyte-related noise-producingcompounds and includes at least one working electrode and a membranesystem (e.g., FIGS. 2E and 2F) that includes at least one domain formedof a silicone-hydrophilic polymer blend with a micellar jacketstructure. In some embodiments, the membrane system includes at leastone additional domain, such as but not limited to an electrode domain,an interference domain, an enzyme domain, a resistance domain and a celldisruptive domain. In one preferred embodiment, the sensor includes amembrane system with a combined resistance-interference domain formed ofthe silicone-hydrophilic polymer blend (with a micellar jacketstructure) is configured to modulate the flux of the analyte into themembrane system and reduce non-constant noise by blocking the passage ofat least one interferent (e.g., acetaminophen) into the membrane system.

In some preferred embodiments, the analyte sensor (e.g., an enzyme-basedelectrochemical analyte sensor) includes at least one working electrodeand a membrane system with a resistance domain configured tosubstantially consume and/or block at least one intermittentnon-constant noise-causing species produced by the host's metabolicprocesses (e.g., H₂O₂ from sources outside the sensor), such that thesignal contribution due to the non-constant non-analyte component isless than about 20% over a period of about one or more days. In morepreferred embodiments, the non-constant non-analyte component is lessthan about 20% over a period of about 1, 2, 3, 4, 5, 6 or 7 days, orlonger. In some preferred embodiments, the non-constant noise is lessthan about 18%, 16%, 14%, 12%, 10%, 8%, 6%, 5%, 4%, 3%, 2%, or 1% orless of the total signal for at least about one day.

In preferred embodiments, the resistance domain is configured to consumeand/or block small molecule interferents caused by the host's metabolicprocesses, such as but not limited to externally generated H₂O₂,reactive oxygen and nitrogen species, such as by rendering theinterferents electrochemically inactive at the sensor's applied voltage.For example, reactive oxygen and nitrogen species (e.g., oxygen andnitrogen radicals) and externally generated H₂O₂ (e.g., derived fromlocal immune cells that have invaded the sensor locality as part of thewound healing process) are highly reactive and spontaneously react withanything that they contact, such as the materials of the membranesystem. Thus, as these small molecule interferents diffuse through themembrane system, only a portion of the them diffuse all of the way tothe sensor's electroactive surface. The remaining small moleculeinterferents, generally, bump into and react with the matrix of themembrane system. When these interferents react with the matrix, they aregenerally oxidized/reduced, such that they are no longer substantiallyreactive with the sensor's electroactive surface at the applied voltage.For example, the reactive oxygen species 02² can be oxidized to O₂.Accordingly, reducing the number of interferent molecules reaching theelectroactive surface can decrease the noise component and increase thesignal-to-noise ratio. Thus the systems of the preferred embodiments areenabled to provide a signal, wherein the substantially non-constantnon-analyte-related component does not substantially contribute to thesignal. For example, in some embodiments, the non-constant noise is lessthan about 20% of the total signal for at least about one day.

In some embodiments, the resistance domain is configured to provide atortuous pathway for noise causing compounds, such that the reactiveelectroactive species, which can interfere with the analyte signal,contact the tortuous diffusion path and are thereby consumed (e.g.,rendered electrochemically inactive at the electroactive surface at theapplied voltage). In some embodiments, a resistance domain and/ormembrane system thickness is configured, such that the non-constantnoise component of the signal is less than about 20% of the total signalover a period of at least about 1, 2 or 3 days, or longer due toself-annihilation of some relatively unstable electroactive compounds asthey diffuse there through. In some embodiments, the thickness of theresistance domain is from about 1 μm to about 25 μm or more. In someembodiments, the thickness of the membrane system is from about 5 μm toabout 10 μm or more. In alternative embodiments, the resistance domainis configured to consume at least one interferent (e.g., reactive oxygenor nitrogen species, externally derived H₂O₂) by inclusion of a compoundthat binds and/or metabolizes the interferent, such that the interferentis rendered substantially electrochemically unreactive with theelectroactive surface (at the applied voltage). In some embodiments, anenzyme, such as but not limited to a peroxidase (e.g., catalase,horseradish peroxidase, cytochrome c peroxidase, glutathione peroxidase,and the like) is incorporated into the resistance domain. In oneexemplary embodiment, a peroxidase disposed in the resistance domain canmetabolize externally generated H₂O₂ (diffusing into the membranesystem) to water and molecular oxygen, which do not substantiallyinteract with the sensor's electroactive surfaces. Thus, substantiallyonly H₂O₂ produced within the enzyme domain (e.g., from the metabolismof glucose by GOX) diffuses to the sensor electroactive surface andproduces a signal; accordingly, a desired thickness of the resistancedomain and/or membrane system can be achieved by a variety of knowntechniques, such as applying one or more additional layers of resistancedomain material during membrane system construction (e.g., 2-layersinstead of 1-layer).

In some embodiments, the resistance domain includes one or more Hemecompounds, which are well known anti-oxidants that react with reactiveinterfering species (which renders the interferent unreactive with theelectroactive surface), such that the non-constant noise component isless than about 20% of the total signal for about one or more days.Suitable Heme compounds include but are not limited to hemin,metmyoglobin, hemoglobin, methemoglobin, and cytochrome c,desferroxamine, or synthesized by partial denaturing and crosslinking toa polymer backbone.

Interferent Scavenging

In some embodiments, the signal-to-noise ratio can be increased byincluding an interferent scavenger in one or more layers of the membranesystem. Depending upon the nature of the interferent, the interferentscavenger can be incorporated into a membrane domain either more distalor proximal to the electroactive surfaces than the enzyme domain; insome embodiments, the scavenger can be incorporated into the membrane'senzyme domain. For example, some interferents are ionic and bind toionic interferents. Accordingly, incorporating interferent-scavengingionic components, such as Nation®, into one or more layers of themembrane system can substantially block and/or slow diffusion of aninterferent having the same charge as the ionic component through themembrane system, in some embodiments. Thus, less interferent reaches theelectroactive surfaces and noise is reduced.

An interferent-scavenging enzyme can be incorporated into one or morelayers of the membrane system. Useful enzymes include but are notlimited to peroxidases and/or oxidases. In general, a peroxidasecatalyzes the reduction of a compound using H₂O₂. Exemplary peroxidasesinclude horseradish peroxidase, glutathione peroxidase, cytochrome Cperoxidase, myeloperoxidase, and the like. Horseradish peroxidase is apreferred peroxidase because interferents present in biological fluids,such as ascorbate, urate, acetaminophen, bilirubin and cysteine, arerapidly oxidized by hydrogen peroxide in the presence of horseradishperoxidase. In general, an oxidase catalyzes the oxidation/reduction ofa compound using molecular O₂. Exemplary oxidases include glucoseoxidase, monoamine oxidase, cytochrome P450 oxidase, NADPH oxidase,cytochrome C oxidase, Xanthine oxidase, L-gulonolactone oxidase, lactateoxidase, lysyl oxidase, catalase and the like. In some embodiments, theperoxidase can be crosslinked to one or more membrane domains usingknown protein cross-linking techniques, such as but not limited toglutaraldehyde cross-linking, NaIO₄, oxidation of enzyme oligosaccharidegroups followed by coupling to the matrix. Some useful coupling methodsare described in U.S. Pat. Nos. 5,262,305 and 5,356,786.

In one exemplary embodiment, a peroxidase is incorporated into a distalmembrane domain (e.g., above the enzyme domain) to remove H₂O₂ derivedfrom external sources (e.g., from macrophages during wound healing). Inone exemplary embodiment, a distal membrane domain includeshorseradish-peroxidase. Additional scavenging techniques are describedin U.S. Pat. Nos. 5,356,786, 6,284,478, and 7,003,341.

In some embodiments, non-constant noise can be decreased by includingone or more membrane domains with an interferent-blocking compound. Avariety of interferent-blocking compounds can be used, such as but notlimited to sulfonated polyether sulfone, polyamino-phenol orpolypyrrole. In one embodiment, the membrane system includes3-amino-phenol, which allows the diffusion of H₂O₂ while blocking thetransport of acetaminophen. Interferent-blocking compounds can beapplied to the electrodes using any method know in the art, such as butnot limited to dipping, spraying, electro-polymerization, spin coatingand the like, as are discussed elsewhere herein. In one exemplaryembodiment, the sensor is a glucose sensor comprising two workingelectrodes, wherein a solution of 3-amino-phenol is sprayed onto theworking electrodes and dried prior to the application of the membraneenzyme domain. In a further embodiment, the sensor includes additionalmembrane layers. Additional methods and devices can be found in U.S.Pat. No. 7,120,483, to Russell, which is incorporated herein byreference in its entirety.

Other systems and methods for reducing or eliminating interferencespecies that can be applied to the membrane system of the preferredembodiments are described in U.S. Patent Publication No.US-2005-0115832-A1, U.S. Patent Publication No. US-2005-0176136-A1, U.S.Patent Publication No. US-2005-0161346-A1, and U.S. Patent PublicationNo. US-2005-0143635-A1. In some alternative embodiments, a distinctinterference domain is not included.

Outer Hydrophilic Surface

In some embodiments, the membrane system is configured with ahydrophilic outer surface (and/or domain) that is at leastdiscontinuously hydrophilic, and can be continuously hydrophilic in someembodiments, configured to contact the host's tissue. The term“discontinuous(ly) hydrophilic surface (domain)” as used herein is abroad phrase, and is to be given its ordinary and customary meaning to aperson of ordinary skill in the art (and it is not to be limited to aspecial or customized meaning), and refers without limitation to asurface including some hydrophilic and some hydrophobic domains locatedthereon. While not wishing to be bound by theory, it is believed thatthe outer surface of the resistance domain is responsible for asubstantial portion of the domain's analyte resistance capability. It isbelieved that the signal-to-noise ratio can be rendered substantiallyunaffected by non-constant noise by providing an at least discontinuoushydrophilic outer surface, such as by surface-treatment with a polymerhaving a sufficient hydrophilic component so as to provide an outersurface with at least discontinuous hydrophilic characteristics and/orby application of a distal discontinuous hydrophilic layer or domainformed of a polymer having a substantial hydrophilic component. Such asurface treatment and/or discontinuously hydrophilic domain outersurface enables a sensor system with an analyte component of at leastabout 80% of the total signal.

In some embodiments, a discontinuously hydrophilic outer domain having asurface with discontinuous hydrophilic components (e.g., either theresistance domain itself or applied in addition to the resistance domainin the exemplary embodiments), configured such that the analytecomponent of the sensor's signal is at least about 80% of the totalsignal for at least about one day. In some embodiments, adiscontinuously hydrophilic outer domain includes a silicone/hydrophilicpolymer blend. For example, in some embodiments, the hydrophiliccomponent of the silicone/hydrophilic polymer blend is at least about 5wt. %. In some preferred embodiments, the hydrophilic component of thesilicone/hydrophilic polymer blend is at least about 10 wt. %. In somepreferred embodiments, the hydrophilic component of thesilicone/hydrophilic polymer blend is at least about 15 wt. %. In evenmore preferred embodiments, the hydrophilic component of thesilicone/hydrophilic polymer blend is at least about 20 wt. %. In stillother more preferred embodiments, the hydrophilic component of thesilicone/hydrophilic polymer blend is at least about 25 wt. %.

In some embodiments, the discontinuously hydrophilic outer domainincludes a surface-treated resistance domain, wherein the outer surfaceof the resistance domain has been configured, such that thehydrophilicity of the resistance domain's surface is increased to suchan extent that the analyte component is at least 80% of the total signalfor at least about one day. In some embodiments, the discontinuouslyhydrophilic outer domain includes a polyurethane-based resistance domainthat has been surface-treated with a polymer containing hydrophilicmoieties (e.g., PEG compounds, Pluronic compounds or a substantiallyhydrophilic polyurethane compound). In some embodiments, the appliedpolymer solution, which is applied over the polyurethane-basedresistance domain 48 (which was substantially cured), forms a cellimpermeable domain 42, as described elsewhere herein. In someembodiments, the applied solution is composed of PEG in acetone, such asbut not limited to a 1%, 5%, 10%, 20%, 30%, 40% or more solution of PEGin acetone, is applied. For example, in experiments usingsmall-structured sensors (e.g., transcutaneous) dipped one time in a 30%solution of PEG in acetone, sensitivity of the treated sensors increasedfrom about 20% to about 75% when compared with non-treated sensors.

In some embodiments, the discontinuously hydrophilic outer domain (e.g.,having a discontinuously hydrophilic outer surface) is formed frompolyurethane. To adjust the glucose permeability through apolyurethane-based outer hydrophilic domain, the amount of hydrophiliccomponent can be adjusted, such that the analyte component of the totalsignal is at least about 80%. For example, in some embodiments, ananalyte sensor includes an outer discontinuously hydrophilic domainformed of a blend of polyurethanes, wherein the percentage of the morehydrophilic polyurethane is selected such that the analyte component ofthe total signal is at least 80% or more. In some embodiments of theanalyte sensor, the discontinuously hydrophilic outer domain is aresistance domain, which is formed of a polyurethane blend that includesa sufficient percentage of a hydrophilic polyurethane (e.g., apolyurethane having hydrophilic groups, such as but not limited to PEG,PEO, PVP) to provide a signal in which the analyte component is at least80% of the total signal, such as for a period of at least about one day.In some preferred embodiments, the hydrophilic component is at leastabout 5% or more of the intermittently hydrophilic outer domain. In someembodiments, the hydrophilic component of the outer intermittentlyhydrophilic outer domain is at least about 1%, 2%, 5%, 7%, 10%, 15%, 20%or 25% or more of the polyurethane blend.

In still other embodiments, a surface of the resistance domain surfaceis treated (e.g., coated) with a polymer having a sufficient number ofhydrophilic moieties, such that the analyte component is at least 80% ofthe total signal. In one exemplary embodiment, a resistance domain of apolyurethane blend is treated with a hydrophilic polymer such as but notlimited to Pluronic® (available from BASF Corp., Florham Park, N.J.,USA) or a sufficiently hydrophilic polyurethane-based polymer. Inanother exemplary embodiment, the sensor is dipped into PEG or PVP toincrease the glucose-permeability of the resistance domain. Other knownhydrophiles, such as those described in the sections entitled“Silicone/Hydrophilic Polymer Materials,” can be used to increase theglucose permeability of the resistance domain without substantiallyaffecting the permeability of interferents. In some embodiments, inwhich the surface of the resistance domain is treated with a hydrophilicpolymer, the analyte component of the signal is at least 90% of thetotal signal. In preferred embodiments, the analyte component of thesignal is at least 99% of the total signal. In preferred embodiments,the analyte component of the signal is at least 80% of the total signalfor at least about one or more days.

These principles and/or resistance domain configurations find use with avariety of other analyte sensors, such as but not limited to thosesensors described in U.S. Pat. Nos. 6,721,587; 4,484,987; 4,671,288;5,322,063; 6,654,625; 6,689,265; and U.S. Patent Publication No.US-2003-0031699-A1.

Fluid Pocket Formation

While not wishing to be bound by theory, it is believed thatnon-constant, non-analyte-related noise can be decreased by dilutingand/or removing transient electroactive species that can interfere withthe analyte signal, such as by increasing fluid bulk (e.g., a fluidpocket), increasing bulk fluid flow and/or increasing diffusion ratearound at least a portion of the sensor, such as the sensing portion ofthe sensor. Furthermore, a physical spacer can reduce the effect oflymph pooling (e.g., build-up of interfering electroactive species inthe tissue surrounding an implanted sensor) due to local compression(described elsewhere herein) by mechanically maintaining a fluid pocket.Since a spacer can maintain the fluid bulk around the sensor duringlocal compression, the affect of interferant concentration increases canbe suppressed or reduced, thereby reducing noise and promotingheightened sensor function. One preferred embodiment provides a devicehaving an architecture that allows and/or promotes increased fluid bulkand/or increased bulk fluid flow in the area surrounding at least aportion of an implanted sensor in vivo, which is believed to enable asensor signal, wherein the non-constant noise component is at least lessthan about 20% of the total signal over a time period of at least oneday.

A variety of structures can be incorporated into the sensorconfiguration to allow and/or promote (e.g., to stimulate or to promote)fluid bulk, bulk fluid flow, and/or diffusion rate, such as by forming afluid pocket, which can enable a sensor signal in which the non-constantnoise component is less than about 20% of the total signal (for aboutone or more days). These structures can include but are not limited tospacers, meshes, shedding layers, roughened surfaces, machineablematerials, nanoporous materials, shape-memory materials, porous memorymaterials, self-assembly materials, collapsible materials, biodegradablematerials, combinations thereof, and the like. Structures that promoteincreased fluid bulk and/or increased bulk fluid flow can also includebut are not limited to structures that promote fluid influx or efflux(e.g., fluid influx-promoting architecture, fluid efflux-promotingarchitecture), that promote vasodilation (e.g., vasodilatingarchitecture), that promote inflammation (e.g., inflammatoryarchitecture), that promote wound healing or perpetuate wounding (e.g.,wound-healing architecture and wounding architecture, respectively),that promote angiogenesis (e.g., angiogenic architecture), that suppressinflammation (e.g., an anti-inflammatory architecture) or combinationsthereof.

In some embodiments, the sensor includes a physical spacer that isdisposed between the sensor and the surrounding tissue; the spacerallows for a liquid sheath to form around at least a portion of thesensor, such as the area surrounding the electrodes, for example. Afluid sheath can provide a fluid bulk that dilutes or buffersinterferants while promoting glucose and oxygen transport to the sensor.In some embodiments, the spacer is a mesh or optionally a fibrousstructure. Suitable mesh materials are known in the art and includeopen-weave meshes fabricated of biocompatible materials such as but notlimited to PLA, PGA, PP, nylon and the like. Mesh spacers can be applieddirectly to the sensing mechanism or over a biointerface membrane, suchas a porous biointerface membrane disclosed elsewhere herein. Meshspacers can act as a fluid influx- or efflux-promoting structure andprovides the advantage of relatively more rapid fluid movement, mixingand/or diffusion within the mesh to reduce local interferantconcentrations and increasing glucose and oxygen concentrations. Theincreased fluid volume within the mesh can also promote increased fluidmovement in and out of the area, which brings in glucose and oxygenwhile removing or diluting interferants.

In one exemplary embodiment, the sensor is wrapped with a single layerof open weave polypropylene (PP) biocompatible mesh. When the sensor isinserted, the mesh holds the surrounding tissue away from the sensorsurface and allows an influx of extracellular fluid to enter the spaceswithin the mesh, thereby creating a fluid pocket around the sensor.Within the fluid pocket, fluid can mix substantially rapidly asextracellular fluid enters and leaves the fluid pocket or due to hostmovement. Interferants are carried by the fluid and therefore can bemixed and/or diluted. Since the host can wear the sensor for a pluralityof days, sedentary periods will inevitably occur. During these periodsinterferants can accumulate. However, the increased fluid volumeprovided by the mesh can substantially buffer accumulated interferantsuntil the sedentary period ends. When the sedentary period is over, anyaccumulated interferants can be diluted or carried away by an influx orefflux of fluid.

In some embodiments, a mesh can be applied to a sensor eithersymmetrically or asymmetrically. For example, the mesh can be tightlywrapped around the sensor. In another example, a strip of mesh can beapplied to only one side of the sensor. In yet another example, the meshcan form a flat envelope about a few millimeters to about a centimeterwide, with the sensor sandwiched within the envelope. In someembodiments, the mesh can cover only a portion of the sensor, such asthe portion containing the electrochemically reactive surface(s). Inother embodiments, the mesh can cover the entire sensor.

In another alternative embodiment, noise can be reduced by inclusion ofa hydrogel on the surface of at least a portion of the sensor, such asthe sensing region. A hydrogel is a network of super absorbent (they cancontain from about 20 wt. % to about 99 wt. % water, preferably 80 wt. %to over 99 wt. % water) natural or synthetic polymer chains. Hydrogelsare sometimes found as a colloidal gel in which water is the dispersionmedium. Since hydrogels are nonporous, fluid and interferants within thehydrogel move by diffusion. Accordingly, the movement of moleculeswithin hydrogels is relatively slower than that possible withinmesh-based fluid pockets as described above. Optionally, the hydrogelcan be biodegradable. A biodegradable hydrogel can provide a fluidpocket that gradually diminishes and is eventually eliminated by thesurrounding tissue.

In a further embodiment, a hydrogel includes a flexible,water-swellable, film (as disclosed elsewhere herein) having a “dryfilm” thickness of from about 0.05 micron or less to about 20 microns ormore, more preferably from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35,0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 to about 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and more preferablyfrom about 2, 2.5 or 3 microns to about 3.5, 4, 4.5, or 5 microns. “Dryfilm” thickness refers to the thickness of a cured film cast from acoating formulation by standard coating techniques. The hydrogelmaterial can be applied to the entire sensor or a portion of it, usingany method known in the art, such as but not limited to dipping,painting, spraying, wrapping, and the like.

In some embodiments, scavenging agents (e.g., bioactive agents that canscavenge, bind-up or substantially inactivate interferants) can beincorporated into the hydrogel or other aspect of the device (e.g.,membrane system). Scavenging agents can suppress prolonged wounding andinflammation by removing signal associated with irritating substancesfrom the locality of the sensor and/or internally generated hydrogenperoxide. One exemplary scavenging agent embodiment incorporates anH₂O₂-degrading enzyme, such as but not limited to glutathione peroxidase(GSH peroxidase), catalase, heme-containing peroxidases, eosinophilperoxidase, thyroid peroxidase or horseradish peroxidase (HRP) into thehydrogel to degrade the available H₂O₂ and produce oxygen. Thescavenging agent can act within the hydrogel or can be released into thelocal environment to act outside the hydrogel.

In some embodiments, a mesh and a hydrogel can be used in combination toprovide greater mechanical support (to hold the surrounding tissue awayfrom the sensor) while slowing down the diffusion rate within themesh-hydrogel layer. For example, a PP mesh can be applied to the sensorfollowed by spraying a dry hydrogel material onto the PP-wrapped sensor.Alternatively, the hydrogel can be dried within the mesh beforeapplication to the sensor. Upon sensor implantation, the hydrogel canabsorb fluid from the surrounding tissue, expand and fill the meshpores. In a further example, the hydrogel can be biodegradable. In thisexample, the hydrogel can initially slow fluid movement. But as thehydrogel is biodegraded, the pores of the mesh are opened up and fluidmovement can speed up or increase.

A variety of alternative materials can be used to create architecturesthat create a fluid pocket. For example, shape-memory materials can beused as an alternative to a mesh, to form a fluid pocket around thesensor. Shape-memory materials are metals or polymers that “remember”their geometries. Shape-memory metals (e.g., memory metals or smartwire) include copper-zinc-aluminum, copper-aluminum-nickel, andnickel-titanium (NiTi) alloys. Shape-memory polymers include materialssuch as polynorbornene, segmented poly(epsilon-caprolactone)polyurethanes, poly(ethylene glycol)-poly(epsilon-caprolactone) diblockcopolymers, and the like, for example. A shape-memory material can bedeformed from its “original” conformation and regains its originalgeometry by itself in response to a force, such as temperature orpressure.

In some embodiments, a porous memory material that has been collapsedinto a flat, nonporous sheet can be applied to the exterior of thesensor as a flat film. After insertion into the body, increasedtemperature or moisture exposure can stimulate the memory material totransform to a 3-dimensional, porous architecture that promotes fluidpocket formation, for example.

In some embodiments, nanoporous materials, which act as molecularsieves, can be used to exclude interferants surrounding the sensor. Inanother alternative embodiment, a swellable material (e.g., a materialhaving an initial volume that absorbs fluid, such as water, when itcontacts the fluid to become a second volume that is greater than theinitial volume) or collapsible material (e.g., a material having aninitial volume that collapse to a second volume that is smaller than theinitial volume) can produce or maintain a fluid pocket.

In some embodiments, materials with differing characteristics can beapplied in combination, such as alternating bands or layers, to suppressuniform capsule formation. For example, alternating bands of collapsibleand non-collapsible swellable material can be applied around a portionof the sensor. Upon implantation, both materials swell with fluid fromthe surrounding tissue. However, only the segments of collapsiblematerial can deform. Since the material surrounding the sensor will beirregular, it can disrupt formation of a continuous cell layer, therebyreducing noise and extending sensor life.

In addition to providing a physical spacer, mesh, porous material or thelike, irritating sensor configurations can reduce noise by promotingfluid pocket formation and/or increased bulk fluid flow. Accordingly,one embodiment of an irritating biointerface includes a structure havinga roughened surface, which can rub or poke adjacent cells in vivo. Thesensor surface can be roughened by coating the sensor with a machineablematerial that is or can be etched to form ridges, bristles, spikes,grids, grooves, circles, spirals, dots, bumps, pits or the like, forexample. The material can be any convenient, biocompatible material,such as machined porous structures that are overlaid on the sensor, suchas but not limited to machineable metal matrix composites, bonesubstrates such as hydroxyapatite, coral hydroxyapatite and β-tricalciumphosphate (TCP), porous titanium (Ti) mixtures made by sintering ofelemental powders, bioglasses (calcium and silicon-based porous glass),ceramics and the like. The material can be “machined” by any convenientmeans, such as but not limited to scraping, etching, lathing orlasering, for example.

Micro-motion of the sensor can increase the irritating effect of aroughened surface. Micro-motion is an inherent property of any implanteddevice, such as an implanted glucose sensor. Micro-motion of the device(e.g., minute movements of the device within the host) is caused by hostmovements, ranging from breathing and small local muscle movements togross motor movements, such as walking, running or even getting up andsitting down. External forces, such as external pressure application,can also cause micro-motion. Micro-motion includes movement of thesensor back and forth, rotation, twisting and/or turning. Accordingly,as the sensor is moved by micro-motion, the sensor's rough surface canrub more vigorously against the surrounding tissue, causing increased orextended wounding, resulting in additional stimulation of the woundhealing process and increases in fluid bulk, bulk fluid flow and/orfluid pocket formation, with a concomitant reduction in noise.

In some embodiments, an irritating architecture is formed fromself-assembly materials. Self-assembly biomaterials comprise specificpolypeptides that are designed a priori to self-assemble into targetednano- and microscopic structures. Intramolecular self-assemblingmolecules are often complex polymers with the ability to assemble fromthe random coil conformation into a well-defined stable structure(secondary and tertiary structure). A variety of self-assembly materialsknown in the art can find use in the present embodiment. For example,PuraMatrix™ (3DM Inc., Cambridge, Mass., USA) can be used to createsynthetic self-assembling peptide nanofiber scaffolds and defined 3-Dmicroenvironments.

In an exemplary embodiment of an irritating biointerface, an irritatingsuperstructure is applied to the working electrode or the completedsensor. A “superstructure,” as used herein is a broad term and used inits ordinary sense, including, without limitation, to refer to anystructure built on something else, such as but not limited to theoverlying portion of a structure. An irritating superstructure caninclude any substantial structure that prevents cell attachment and isirritating to the surrounding tissue in vivo. In one example, anirritating superstructure can include large spaces, such as at leastabout 50 μm wide and at least about 50 μm deep. Cells surrounding thesensor can be prevented from attachment in the spaces within thesuperstructure, allowing fluid to fill these spaces. In some exemplaryembodiments, an irritating superstructure takes advantage of sensormicromotion, to prevent cell attachment and stimulate fluid pocketformation.

In one exemplary embodiment, an irritating superstructure is comprisedof ridges at least about 0.25 μm to 0.50 μm in diameter and about 50 μmhigh, and separated by at least about 0.25 μm to 0.50 μm. In anotherexemplary embodiment, an exposed silver wire, at least about 0.25 μm to0.50 μm in diameter, is applied to the sensor exterior to form groovesabout 50 μm wide and about 50 μm deep. Since silver is pro-inflammatoryand stimulates fluid influx from the surrounding tissues, thecombination of an irritating superstructure and a chemical irritantcould promote an increased rate of fluid influx or prolong irritationand fluid influx. In yet another exemplary embodiment, with reference tothe embodiment shown in FIG. 2A, the configuration (e.g., diameter) ofthe reference electrode 30 can be changed (e.g., increased in sizeand/or coil spacing) such that the reference electrode, itself, becomesan irritating superstructure.

Porous Membrane

In addition to the devices described above, fluid bulk and or bulk fluidflow at and/or adjacent to the sensor can be increased by incorporatinga porous membrane into the sensor system, such that noise issubstantially reduced and sensor accuracy and/or sensitivity areimproved. A porous membrane can be referred to as a “bioprotectivedomain” or a “cell disruptive domain.” In some embodiments, the sensorincludes a porous material disposed over some portion thereof, whichmodifies the host's tissue response to the sensor and thereby reducesnoise (e.g., due to a local build up of electroactive species that caninterfere with the analyte signal). For example, in some embodiments,the porous material surrounding the sensor advantageously enhances andextends sensor performance and lifetime in the short-term by slowing orreducing cellular migration to the sensor and associated degradationthat would otherwise be caused by cellular invasion if the sensor weredirectly exposed to the in vivo environment. Alternatively, the porousmaterial can provide stabilization of the sensor via tissue ingrowthinto the porous material in the long-term. Suitable porous materialsinclude silicone, polytetrafluoroethylene, expandedpolytetrafluoroethylene, polyethylene-co-tetrafluoroethylene,polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene,homopolymers, copolymers, terpolymers of polyurethanes, polypropylene(PP), polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polyvinylalcohol (PVA), polybutylene terephthalate (PBT), polymethylmethacrylate(PMMA), polyether ether ketone (PEEK), polyamides, polyurethanes,cellulosic polymers, poly(ethylene oxide), poly(propylene oxide) andcopolymers and blends thereof, polysulfones and block copolymers thereofincluding, for example, di-block, tri-block, alternating, random andgraft copolymers, as well as metals, ceramics, cellulose, hydrogelpolymers, poly (2-hydroxyethyl methacrylate, pHEMA), hydroxyethylmethacrylate, (HEMA), polyacrylonitrile-polyvinyl chloride (PAN-PVC),high density polyethylene, acrylic copolymers, nylon, polyvinyldifluoride, polyanhydrides, poly(l-lysine), poly (L-lactic acid),hydroxyethylmethacrylate, hydroxyapeptite, alumina, zirconia, carbonfiber, aluminum, calcium phosphate, titanium, titanium alloy, nintinol,stainless steel, and CoCr alloy, or the like, such as are described inU.S. Patent Publication No. US-2005-0031689-A1 and U.S. PatentPublication No. US-2005-0112169-A1.

In some embodiments, the porous material surrounding the sensor providesunique advantages in the short-term (e.g., one to 14 days) that can beused to enhance and extend sensor performance and lifetime. However,such materials can also provide advantages in the long-term too (e.g.,greater than 14 days). Particularly, the in vivo portion of the sensor(the portion of the sensor that is implanted into the host's tissue) isencased (partially or fully) in a porous material. The porous materialcan be wrapped around the sensor (for example, by wrapping the porousmaterial around the sensor or by inserting the sensor into a section ofporous material sized to receive the sensor). Alternately, the porousmaterial can be deposited on the sensor (for example, by electrospinningof a polymer directly thereon). In yet other alternative embodiments,the sensor is inserted into a selected section of porous biomaterial.Other methods for surrounding the in vivo portion of the sensor with aporous material can also be used as is appreciated by one skilled in theart.

The porous material surrounding the sensor advantageously slows orreduces cellular migration to the sensor and associated degradation thatwould otherwise be caused by cellular invasion if the sensor weredirectly exposed to the in vivo environment. Namely, the porous materialprovides a barrier that makes the migration of cells towards the sensormore tortuous and therefore slower (providing short-term advantages). Itis believed that this reduces or slows the sensitivity loss normallyobserved in a short-term sensor over time.

In an embodiment wherein the porous material is a high oxygen solubilitymaterial, such as porous silicone, the high oxygen solubility porousmaterial surrounds some of or the entire in vivo portion of the sensor.In some embodiments, a lower ratio of oxygen-to-glucose can besufficient to provide excess oxygen by using a high oxygen solubledomain (for example, a silicone- or fluorocarbon-based material) toenhance the supply/transport of oxygen to the enzyme membrane and/orelectroactive surfaces. It is believed that some signal noise normallyseen by a conventional sensor can be attributed to an oxygen deficit.Silicone has high oxygen permeability, thus promoting oxygen transportto the enzyme layer. By enhancing the oxygen supply through the use of asilicone composition, for example, glucose concentration can be less ofa limiting factor. In other words, if more oxygen is supplied to theenzyme and/or electroactive surfaces, then more glucose can also besupplied to the enzyme without creating an oxygen rate-limiting excess.While not being bound by any particular theory, it is believed thatsilicone materials provide enhanced bio-stability when compared to otherpolymeric materials such as polyurethane.

In certain aspects, including a biointerface structure, material,matrix, and/or membrane that creates a space appropriate for fillingwith fluid in vivo on a sensor can enhance sensor performance. In someembodiments, a sensor includes a porous biointerface material, whichallows fluid from the surrounding tissues to form a fluid-filled pocketaround at least a portion of the sensor. It is believed that thefluid-filled pocket provides a sufficient source of analyte-containingfluid for accurate sensor measurement in the short-term. Additionally oralternatively, inclusion of bioactive agents can modify the host'stissue response, for example to reduce or eliminate tissue ingrowth orother cellular responses into the biointerface.

In some aspects, modifying a sensor with a structure, material, and/ormembrane/matrix that allows tissue ingrowth without barrier cellformation can enhance sensor performance. For example, a vascularizedbed of tissue for long-term analyte sensor measurement. In someembodiments, a porous biointerface membrane, including a plurality ofinterconnected cavities and a solid portion, covering at least thesensing portion of a sensor allows vascularized tissue ingrowth therein.Vascularized tissue ingrowth provides a sufficient source ofanalyte-containing tissue in the long-term. Additionally oralternatively, inclusion of bioactive agents can modify the host'stissue response, for example to reduce or eliminate barrier cell layerformation within the membrane.

When used herein, the terms “membrane” and “matrix” are meant to beinterchangeable. In these embodiments first domain is provided thatincludes an architecture, including cavity size, configuration, and/oroverall thickness, that modifies the host's tissue response, forexample, by creating a fluid pocket, encouraging vascularized tissueingrowth, disrupting downward tissue contracture, resisting fibroustissue growth adjacent to the device, and/or discouraging barrier cellformation. The biointerface preferably covers at least the sensingmechanism of the sensor and can be of any shape or size, includinguniform, asymmetrically, or axi-symmetrically covering or surrounding asensing mechanism or sensor.

In some embodiments, a second domain is optionally provided that isimpermeable to cells and/or cell processes. A bioactive agent isoptionally provided that is incorporated into the at least one of thefirst domain, the second domain, the sensing membrane, or other part ofthe implantable device, wherein the bioactive agent is configured tomodify a host tissue response.

In one embodiment, a porous material that results in increased fluidbulk, bulk fluid flow and/or diffusion rate, as well as formation ofclose vascular structures, is a porous polymer membrane, such as but notlimited to polytetrafluoroethylene (PTFE), polysulfone, polyvinylidenedifluoride, polyacrylonitrile, silicone, polytetrafluoroethylene,expanded polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene,polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene,homopolymers, copolymers, terpolymers of polyurethanes, polypropylene(PP), polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polyvinylalcohol (PVA), polybutylene terephthalate (PBT), polymethylmethacrylate(PMMA), polyether ether ketone (PEEK), polyamides, polyurethanes,cellulosic polymers, poly(ethylene oxide), poly(propylene oxide) andcopolymers and blends thereof, polysulfones and block copolymers thereofincluding, for example, di-block, tri-block, alternating, random andgraft copolymers, as well as metals, ceramics, cellulose, hydrogelpolymers, poly (2-hydroxyethyl methacrylate, pHEMA), hydroxyethylmethacrylate, (HEMA), polyacrylonitrile-polyvinyl chloride (PAN-PVC),high density polyethylene, acrylic copolymers, nylon, polyvinyldifluoride, polyanhydrides, poly(l-lysine), poly (L-lactic acid), andhydroxyethylmethacrylate, having an average nominal pore size of atleast about 0.6 μm to 20 μm, using conventional methods fordetermination of pore size in the trade. In one embodiment, at leastapproximately 50% of the pores of the membrane have an average size ofapproximately 0.6 μm to about 20 μm, such as described in U.S. Pat. No.5,882,354. In this exemplary embodiment, the structural elements, whichprovide the three-dimensional conformation, can include fibers, strands,globules, cones or rods of amorphous or uniform geometry that is smoothor rough. These elements, hereafter referred to as “strands,” have ingeneral one dimension larger than the other two and the smallerdimensions do not exceed five microns.

In another further embodiment, the porous polymer membrane material, asdescribed above, consists of strands that define “apertures” formed by aframe of the interconnected strands. The apertures have an average sizeof no more than about 20 μm in any but the longest dimension. Theapertures of the material form a framework of interconnected apertures,defining “cavities” that are no greater than an average of about 20 μmin any but the longest dimension. In another embodiment the porouspolymer membrane material has at least some apertures having asufficient size to allow at least some vascular structures to be createdwithin the cavities. At least some of these apertures, while allowingvascular structures to form within the cavities, prevent connectivetissue from forming therein because of size restrictions.

In a further embodiment, the porous membrane has frames of elongatedstrands of material that are less than 5 microns in all but the longestdimension and the frames define apertures which interconnect to formthree-dimensional cavities which permit substantially all inflammatorycells migrating into the cavities to maintain a rounded morphology.Additionally, the porous material promotes vascularization adjacent butnot substantially into the porous material upon implantation into ahost. Exemplary materials include but are not limited to polyethylene,polypropylene, polytetrafluoroethylene (PTFE), cellulose acetate,cellulose nitrate, polycarbonate, polyester, nylon, polysulfone, mixedesters of cellulose, polyvinylidene difluoride, silicone,polyacrylonitrile, and the like.

In some embodiments, a short-term sensor is provided with a spaceradapted to provide a fluid pocket between the sensor and the host'stissue. It is believed that this spacer, for example a biointerfacematerial, matrix, mesh, hydrogel and like structures and the resultantfluid pocket provide for oxygen and/or glucose transport to the sensor.

In one exemplary embodiment, the sensor includes a biointerface membraneconfigured to prevent adipose cell contact with an insertedtranscutaneous sensor or an implanted sensor. Preferably, a porousbiointerface membrane surrounds the sensor, covering the sensingmechanism (e.g., at least a working electrode) and is configured to fillwith fluid in vivo, thereby creating a fluid pocket surrounding thesensor. Accordingly, the adipose cells surrounding the sensor are held adistance away (such as the thickness of the porous biointerfacemembrane, for example) from the sensor surface. Accordingly, as theporous biointerface membrane fills with fluid (e.g., creates a fluidpocket), oxygen and glucose are transported to the sensing mechanism inquantities sufficient to maintain accurate sensor function.Additionally, as discussed elsewhere herein, interferants are diluted,suppressing or reducing interference with sensor function.

In another exemplary embodiment, a short-term sensor (or short-termfunction of a long-term sensor) including a biointerface, including butnot limited to, for example, porous biointerface materials, mesh cages,and the like, all of which are described in more detail elsewhereherein, can be employed to improve sensor function in the short-term(e.g., first few hours to days), such as by reducing noise on the sensorsignal. Porous biointerface membranes need not necessarily includeinterconnected cavities for creating a fluid pocket in the short-term.

Bioactive Agents

A variety of bioactive agents are known to promote fluid influx orefflux. Accordingly, incorporation of bioactive agents into the membranecan increasing fluid bulk, bulk fluid flow and/or diffusion rates (andpromoting glucose and oxygen influx), thereby decrease non-constantnoise. In some embodiments, fluid bulk and/or bulk fluid flow areincreased at (e.g., adjacent to the sensor exterior surface) the sensorby incorporation of one or more bioactive agents. In some embodiments,the sensor is configured to include a bioactive agent that irritates thewound and stimulates the release of soluble mediators that are known tocause a local fluid influx at the wound site. In some embodiments, thesensor is configured to include a vasodilating bioactive agent, whichcan cause a local influx of fluid from the vasculature.

A variety of bioactive agents can be found useful in preferredembodiments. Exemplary bioactive agents include but are not limited toblood-brain barrier disruptive agents and vasodilating agents,vasodilating agents, angiogenic factors, and the like. Useful bioactiveagents include but are not limited to mannitol, sodium thiosulfate,VEGF/VPF, NO, NO-donors, leptin, bradykinin, histamines, bloodcomponents, platelet rich plasma (PRP), matrix metalloproteinases (MMP),Basic Fibroblast Growth Factor (bFGF), (also known as Heparin BindingGrowth Factor-II and Fibroblast Growth Factor II), Acidic FibroblastGrowth Factor (aFGF), (also known as Heparin Binding Growth Factor-I andFibroblast Growth Factor-I), Vascular Endothelial Growth Factor (VEGF),Platelet Derived Endothelial Cell Growth Factor BB (PDEGF-BB),Angiopoietin-1, Transforming Growth Factor Beta (TGF-Beta), TransformingGrowth Factor Alpha (TGF-Alpha), Hepatocyte Growth Factor, TumorNecrosis Factor-Alpha (TNF-Alpha), Placental Growth Factor (PLGF),Angiogenin, Interleukin-8 (IL-8), Hypoxia Inducible Factor-I (HIF-1),Angiotensin-Converting Enzyme (ACE) Inhibitor Quinaprilat, Angiotropin,Thrombospondin, Peptide KGHK, Low Oxygen Tension, Lactic Acid, Insulin,Leptin, Copper Sulphate, Estradiol, prostaglandins, cox inhibitors,endothelial cell binding agents (for example, decorin or vimentin),glenipin, hydrogen peroxide, nicotine, and Growth Hormone. Still otheruseful bioactive agents include enzymes, cytotoxic or necrosing agents(e.g., pactataxyl, actinomycin, doxorubicin, daunorubicin, epirubicin,bleomycin, plicamycin, mitomycin), cyclophosphamide, chlorambucil,uramustine, melphalan, bryostatins, inflammatory bacterial cell wallcomponents, histamines, pro-inflammatory factors and the like.

Bioactive agents can be added during manufacture of the sensor byincorporating the desired bioactive agent in the manufacturing materialfor one or more sensor layers or into an exterior biomaterial, such as aporous silicone membrane. For example, bioactive agents can be mixedwith a solution during membrane formation, which is subsequently appliedonto the sensor during manufacture. Alternatively, the completed sensorcan be dipped into or sprayed with a solution of a bioactive agent, forexample. The amount of bioactive agent can be controlled by varying itsconcentration, varying the indwell time during dipping, applyingmultiple layers until a desired thickness is reached, and the like, asdisclosed elsewhere herein. In an alternative embodiment, the bioactiveagent is microencapsulated before application to the sensor. Forexample, microencapsulated bioactive agent can be sprayed onto acompleted sensor or incorporated into a structure, such as an outer meshlayer or a shedding layer. Microencapsulation can offer increasedflexibility in controlling bioactive agent release rate, time of releaseoccurrence and/or release duration.

Chemical systems/methods of irritation can be incorporated into anexterior sensor structure, such as the biointerface membrane (describedelsewhere herein) or a shedding layer that releases the irritating agentinto the local environment. For example, in some embodiments, a“shedding layer” releases (e.g., sheds or leaches) molecules into thelocal vicinity of the sensor and can speed up osmotic fluid shifts. Insome embodiments, a shedding layer can provide a mild irritation andencourage a mild inflammatory/foreign body response, thereby preventingcells from stabilizing and building up an ordered, fibrous capsule andpromoting fluid pocket formation.

A shedding layer can be constructed of any convenient, biocompatiblematerial, include but not limited to hydrophilic, degradable materialssuch as polyvinylalcohol (PVA), PGC, Polyethylene oxide (PEO),polyethylene glycol-polyvinylpyrrolidone (PEG-PVP) blends, PEG-sucroseblends, hydrogels such as polyhydroxyethyl methacrylate (pHEMA),polymethyl methacrylate (PMMA) or other polymers with quickly degradingester linkages. In certain embodiment, absorbable suture materials,which degrade to compounds with acid residues, can be used. The acidresidues are chemical irritants that stimulate inflammation and woundhealing. In certain embodiments, these compounds include glycolic acidand lactic acid based polymers, polyglactin, polydioxone, polydyconate,poly(dioxanone), poly(trimethylene carbonate) copolymers, and poly(caprolactone) homopolymers and copolymers, and the like.

In other exemplary embodiments, the shedding layer can be a layer ofmaterials listed elsewhere herein for the first domain, includingcopolymers or blends with hydrophilic polymers such aspolyvinylpyrrolidone (PVP), polyhydroxyethyl methacrylate,polyvinylalcohol, polyacrylic acid, polyethers, such as polyethyleneglycol, and block copolymers thereof including, for example, di-block,tri-block, alternating, random and graft copolymers (block copolymersare discussed in U.S. Pat. No. 4,803,243 and U.S. patent). In onepreferred embodiment, the shedding layer is comprised of polyurethaneand a hydrophilic polymer. For example, the hydrophilic polymer can bepolyvinylpyrrolidone. In one preferred embodiment, the shedding layer ispolyurethane comprising not less than 5 weight percentpolyvinylpyrrolidone and not more than 45 weight percentpolyvinylpyrrolidone. Preferably, the shedding layer comprises not lessthan 20 weight percent polyvinylpyrrolidone and not more than 35 weightpercent polyvinylpyrrolidone and, most preferably, polyurethanecomprising about 27 weight percent polyvinylpyrrolidone.

In other exemplary embodiments, the shedding layer can include asilicone elastomer, such as a silicone elastomer and a poly(ethyleneoxide) and poly(propylene oxide) co-polymer blend, as disclosed incopending U.S. patent application Ser. No. 11/404,417 filed Apr. 14,2006. In one embodiment, the silicone elastomer is a dimethyl- andmethylhydrogen-siloxane copolymer. In one embodiment, the siliconeelastomer comprises vinyl substituents. In one embodiment, the siliconeelastomer is an elastomer produced by curing a MED-4840 mixture. In oneembodiment, the copolymer comprises hydroxy substituents. In oneembodiment, the co-polymer is a triblock poly(ethyleneoxide)-poly(propylene oxide)-poly(ethylene oxide) polymer. In oneembodiment, the co-polymer is a triblock poly(propyleneoxide)-poly(ethylene oxide)-poly(propylene oxide) polymer. In oneembodiment, the co-polymer is a PLURONIC® polymer. In one embodiment,the co-polymer is PLURONIC® F-127. In one embodiment, at least a portionof the co-polymer is cross-linked. In one embodiment, from about 5% w/wto about 30% w/w of the membrane is the co-polymer.

A shedding layer can take any shape or geometry, symmetrical orasymmetrical, to promote fluid influx in a desired location of thesensor, such as the sensor head or the electrochemically reactivesurfaces, for example. Shedding layers can be located on one side ofsensor or both sides. In another example, the shedding layer can beapplied to only a small portion of the sensor or the entire sensor.

In one exemplary embodiment, a shedding layer comprising polyethyleneoxide (PEO) is applied to the exterior of the sensor, where the tissuesurrounding the sensor can directly access the shedding layer. PEOleaches out of the shedding layer and is ingested by local cells thatrelease pro-inflammatory factors. The pro-inflammatory factors diffusethrough the surrounding tissue and stimulate an inflammation responsethat includes an influx of fluid. Accordingly, early noise can bereduced or eliminated and sensor function can be improved.

In another exemplary embodiment, the shedding layer is applied to thesensor in combination with an outer porous layer, such as a mesh or aporous biointerface as disclosed elsewhere herein. In one embodiment,local cells access the shedding layer through the through pores of aporous silicone biointerface. In one example, the shedding layermaterial is applied to the sensor prior to application of the poroussilicone. In another example, the shedding layer material can beabsorbed into the lower portion of the porous silicone (e.g., theportion of the porous silicone that will be proximal to the sensor afterthe porous silicone has been applied to the sensor) prior to applicationof the porous silicone to the sensor.

Wound Suppression

Non-constant noise can be decreased by wound suppression (e.g., duringsensor insertion), in some embodiments. Wound suppression includes anysystems or methods by which an amount of wounding that occurs uponsensor insertion is reduced and/or eliminated. While not wishing to bebound by theory, it is believed that if wounding is suppressed or atleast significantly reduced, the sensor will be surrounded bysubstantially normal tissue (e.g., tissue that is substantially similarto the tissue prior to sensor insertion). Substantially normal tissue isbelieved to have a lower metabolism than wounded tissue, producing fewerinterferants and reducing early noise.

Wounds can be suppressed or minimized by adaptation of the sensor'sarchitecture to one that either suppresses wounding or promotes rapidhealing, such as an architecture that does not cause substantialwounding (e.g., an architecture configured to prevent wounding), anarchitecture that promotes wound healing, an anti-inflammatoryarchitecture, and the like. In one exemplary embodiment, the sensor isconfigured to have a low profile, a zero-footprint or a smooth surface.For example, the sensor can be formed of substantially thin wires, suchas wires from about 50 μm to about 150 μm in diameter, for example.Preferably, the sensor is small enough to fit within a very small gaugeneedle, such as a 30, 31, 32, 33, 34, or 35 gauge needle (or smaller) onthe Stubs scale, for example. In general, a smaller needle, the morereduces the amount of wounding during insertion. For example, a verysmall needle can reduce the amount of tissue disruption and therebyreduce the subsequent wound healing response. In an alterativeembodiment, the sensor's surface is smoothed with a lubricious coating,to reduce wounding upon sensor insertion.

Wounding can also be reduced by inclusion of wound-suppressive agents(bioactive agents) that either reduce the amount of initial wounding orsuppress the wound healing process. While not wishing to be bound bytheory, it is believed that application of a wound-suppressing agent,such as an anti-inflammatory, an immunosuppressive agent, ananti-infective agent, or a scavenging agent, to the sensor can create alocally quiescent environment and suppress wound healing. In a quiescentenvironment, bodily processes, such as the increased cellular metabolismassociated with wound healing, can minimally affect the sensor. If thetissue surrounding the sensor is undisturbed, it can continue its normalmetabolism and promote sensor function.

In some embodiment, useful compounds and/or factors for suppressingwounding include but are not limited to first-generation H₁-receptorantagonists: ethylenediamines (e.g., mepyramine (pyrilamine),antazoline), ethanolamines (e.g., diphenhydramine, carbinoxamine,doxylamine, clemastine, and dimenhydrinate), alkylamines (pheniramine,chlorphenamine (chlorpheniramine), dexchlorphenamine, brompheniramine,and triprolidine), piperazines (cyclizine, hydroxyzine, and meclizine),and tricyclics (promethazine, alimemazine (trimeprazine),cyproheptadine, and azatadine); second-generation H₁-receptorantagonists such as acrivastine, astemizole, cetirizine, loratadine,mizolastine, azelastine, levocabastine, and olopatadine; mast cellstabilizers such as cromoglicate (cromolyn) and nedocromil;anti-inflammatory agents, such as acetometaphen, aminosalicylic acid,aspirin, celecoxib, choline magnesium trisalicylate, diclofenacpotassium, diclofenac sodium, diflunisal, etodolac, fenoprofen,flurbiprofen, ibuprofen, indomethacin, interleukin (IL)-10, IL-6 mutein,anti-IL-6 iNOS inhibitors (e.g., L-NMDA), Interferon, ketoprofen,ketorolac, leflunomide, melenamic acid, mycophenolic acid, mizoribine,nabumetone, naproxen, naproxen sodium, oxaprozin, piroxicam, rofecoxib,salsalate, sulindac, and tolmetin; corticosteroids such as cortisone,hydrocortisone, methylprednisolone, prednisone, prednisolone,betamethesone, beclomethasone dipropionate, budesonide, dexamethasonesodium phosphate, flunisolide, fluticasone propionate, paclitaxel,tacrolimus, tranilast, triamcinolone acetonide, betamethasone,fluocinolone, fluocinonide, betamethasone dipropionate, betamethasonevalerate, desonide, desoximetasone, fluocinolone, triamcinolone,triamcinolone acetonide, clobetasol propionate, and dexamethasone;immunosuppressive and/or immunomodulatory agents such asanti-proliferative, cell-cycle inhibitors (e.g., paclitaxel,cytochalasin D, infiximab), taxol, actinomycin, mitomycin, thospromoteVEGF, estradiols, NO donors, QP-2, tacrolimus, tranilast, actinomycin,everolimus, methothrexate, mycophenolic acid, angiopeptin, vincristing,mitomycine, statins, C MYC antisense, sirolimus (and analogs),RestenASE, 2-chloro-deoxyadenosine, PCNA Ribozyme, batimstat, prolylhydroxylase inhibitors, PPARy ligands (for example troglitazone,rosiglitazone, pioglitazone), halofuginone, C-proteinase inhibitors,probucol, BCP671, EPC antibodies, catchins, glycating agents, endothelininhibitors (for example, Ambrisentan, Tesosentan, Bosentan), Statins(for example, Cerivastatin), E. coli heat-labile enterotoxin, andadvanced coatings; anti-infective agents, such as anthelmintics(mebendazole); antibiotics such as aminoclycosides (gentamicin,neomycin, tobramycin), antifungal antibiotics (amphotericin b,fluconazole, griseofulvin, itraconazole, ketoconazole, nystatin,micatin, tolnaftate), cephalosporins (cefaclor, cefazolin, cefotaxime,ceftazidime, ceftriaxone, cefuroxime, cephalexin), beta-lactamantibiotics (cefotetan, meropenem), chloramphenicol, macrolides(azithromycin, clarithromycin, erythromycin), penicillins (penicillin Gsodium salt, amoxicillin, ampicillin, dicloxacillin, nafcillin,piperacillin, ticarcillin), tetracyclines (doxycycline, minocycline,tetracycline), bacitracin; clindamycin; colistimethate sodium; polymyxinb sulfate; vancomycin; antivirals including acyclovir, amantadine,didanosine, efavirenz, foscarnet, ganciclovir, indinavir, lamivudine,nelfinavir, ritonavir, saquinavir, silver, stavudine, valacyclovir,valganciclovir, zidovudine; quinolones (ciprofloxacin, levofloxacin);sulfonamides (sulfadiazine, sulfisoxazole); sulfones (dapsone);furazolidone; metronidazole; pentamidine; sulfanilamidum crystallinum;gatifloxacin; and sulfamethoxazole/trimethoprim; interferant scavengers,such as superoxide dismutase (SOD), thioredoxin, glutathione peroxidaseand catalase, anti-oxidants, such as uric acid and vitamin C, ironcompounds, Heme compounds, and some heavy metals; artificial protectivecoating components, such as albumin, fibrin, collagen, endothelialcells, wound closure chemicals, blood products, platelet-rich plasma,growth factors and the like.

While not wishing to be bound by theory, it is believed that, inaddition to the analyte sensor configurations described elsewhereherein, application of a lubricious coating to the sensor cansubstantially reduce and/or suppress noise occurrence by substantiallypreventing injury to the host. Accordingly, in some embodiments, alubricious coating can be applied to the in vivo portion of the sensorto reduce the foreign body response to the implanted sensor. The term“lubricous coating” as used herein is a broad term and is used in itsordinary sense, including without limitation, a surface treatment thatprovides a reduced surface friction. A variety of polymers are suitablefor use as a lubricious sensor coating, such as but not limited toTeflon, polyethylene, polycarbonate, polyurethane, poly(ethylene oxide),poly(ethylene oxide)-poly(propylene oxide) copolymers, and the like. Inone exemplary embodiment, one or more layers of HydroMed™, apolyether-polyurethane manufactured by CardioTech International, Inc.(Wilmington, Mass., USA) is applied to the sensor (e.g., over theresistance domain). A more detailed description can be found in Example1, below.

In some embodiments, wounding can be suppressed by inclusion of asilicone coating (e.g., silicon-hydrophilic polymer blend) or ahydrophilic shedding layer can be applied to the sensor. While notwishing to be bound by theory, it is believed that a siliconebioprotective coating or shedding layer can promote formation andmaintenance of a fluid pocket around the sensor, to enhance glucose andfluid transport as well as clearance of interferants. A siliconebioprotective coating can create a local environment with enhancedvascular permeability and/or vascularization. Such a coating is believedto speed up the inflammatory response to achieve a substantiallyconsistent wound environment more quickly than without the coating.Furthermore, a silicone bioprotective coating is believed to be able tosubdue the inflammatory response to reduce production of cellularbyproducts that are believed to be electrochemical interferants.

In one embodiment, a silicone bioprotective coating can consist of oneor more layer(s) formed from a composition that, in addition toproviding high oxygen solubility, allows for the transport of glucose orother such water-soluble molecules (for example, drugs). In oneembodiment, these layers comprise a blend of a silicone polymer with ahydrophilic polymer. For additional description, see the sectionentitled “Silicon/Hydrophilic Polymer Blend Materials” herein andco-pending U.S. patent application Ser. No. 11/404,417, filed Apr. 14,2006, co-pending U.S. patent application Ser. No. 11/675,063, U.S.Patent Publication No. US-2005-0090607-A1, U.S. Patent Publication No.US-2006-0270923-A1, and U.S. Patent Publication No. US-2007-0027370-A1.

Many of the above disclosed methods and structures for forming a fluidpocket, diluting interferants, reducing noise and the like can be usedin combination to facilitate a desired effect or outcome. For example,in one embodiment, a shedding layer composed of a hydrophilic siliconefilm and a necrosing agent can be applied in combination to at least aportion of the sensor. The silicone film can suppress protein adherenceto the sensor surface while the necrosing agent can devitalize a smallportion of tissue adjacent to the sensor, stimulating formation of afluid pocket around the hydrophilic silicone film. Preferably, theincreased volume of fluid surrounding the sensor dilutes interferantswhile the shedding layer provides a physical separation between thesensor and the surrounding tissue.

In another exemplary embodiment, a mesh sprayed with dexamethasone iswrapped around the exterior of the sensor. The mesh can provide aphysical spacer for a fluid pocket while the dexamethasone inhibitsinflammation. Preferably, fluid can fill the mesh and the dexamethasonecan promote normal tissue metabolism around the sensor by inhibiting aninflux of inflammatory cells. Consequently, glucose and oxygen cantravel freely between the tissue and the sensor through the fluid filledmesh without a buildup of interferants, even during periods of tissuecompression, thereby promoting sensor sensitivity and thereby reducingnoise.

Additional description of increasing fluid bulk, by adapting thesensor's configuration can be found in co-pending U.S. PatentPublication No. US-2006-0229512-A1 and co-pending U.S. patentapplication Ser. No. 11/654,140 filed on Jan. 17, 2007.

Auxiliary Electrode

In some circumstances, non-constant noise can be reduced byincorporating into the sensor system an auxiliary electrode configuredto electrochemically modify (for example, oxidize or reduce)electrochemical interferants to render them substantiallynon-electroactively reactive at the electroactive sensing surface(s) inorder to overcome the effects of interferants on the working electrode.It is known that many electrochemical interferants can be reduced at apotential of from about +0.1V to about +1.2V or more; for example,acetaminophen is reduced at a potential of about +0.4 V. It is notedthat one challenge to generating oxygen electrochemically in this way isthat while an auxiliary electrode does produce excess oxygen, theplacement of the auxiliary electrode in proximity to theanalyte-measuring working electrode can cause oxidation of hydrogenperoxide at the auxiliary electrode, resulting in reduced signals at theworking electrode. Accordingly, the sensors of preferred embodimentsplace an auxiliary electrode above the electrode system, or otherelectroactive sensing surface, thereby reducing or eliminating theproblem of inaccurate signals as described above.

Preferably, the auxiliary electrode is located within or adjacent to themembrane system, for example, between the enzyme and other domains,although the auxiliary electrode can be placed anywhere between theelectroactive sensing surface and the outside fluid. The auxiliaryelectrode is formed from known working electrode materials (for example,platinum, palladium, graphite, gold, carbon, conductive polymer, or thelike) and has a voltage setting that produces oxygen (for example, fromabout +0.6 V to about +1.2 V or more) and/or that electrochemicallymodifies (for example, reduces) electrochemical interferants to renderthem substantially non-reactive at the electroactive sensing surface(s)(for example, from about +0.1 V to about +1.2 V or more). The auxiliaryelectrode can be a mesh, grid, plurality of spaced wires or conductivepolymers, or other configurations designed to allow analytes topenetrate therethrough.

In another aspect of the preferred embodiments, the auxiliary electrodeis configured to electrochemically modify (for example, oxidize orreduce) electrochemical interferants to render them substantiallynon-reactive at the electroactive sensing surface(s). In theseembodiments, which can be in addition to or alternative to theabove-described oxygen-generating embodiments, a polymer coating ischosen to selectively allow interferants (for example, urate, ascorbate,and/or acetaminophen such as described in U.S. Pat. No. 6,579,690) topass through the coating and electrochemically react with the auxiliaryelectrode, which effectively pre-oxidizes the interferants, renderingthem substantially non-reactive at the working electrode. In oneexemplary embodiment, silicone materials can be synthesized to allow thetransport of oxygen, acetaminophen and other interferants, but not allowthe transport of glucose. In some embodiments, the polymer coatingmaterial can be chosen with a molecular weight that blocks glucose andallows the transport of oxygen, urate, ascorbate, and acetaminophen. Inanother exemplary embodiment, silicone materials can be synthesized toallow the transport of oxygen, glucose, acetaminophen, and otherinterferants. In some embodiments, the polymer coating material ischosen with a molecular weight that allows the transport of oxygen,glucose, urate, ascorbate, and acetaminophen. The voltage settingnecessary to react with interfering species depends on the targetelectrochemical interferants, for example, from about +0.1 V to about+1.2 V. In some embodiments, wherein the auxiliary electrode is set at apotential of from about +0.6 to about +1.2 V, both oxygen-generation andelectrochemical interferant modification can be achieved. In someembodiments, wherein the auxiliary electrode is set at a potential belowabout +0.6 V, the auxiliary electrode will function mainly toelectrochemically modify interferants, for example. Additionaldescription can be found in U.S. Pat. No. 7,074,307.

Sensor Electronics

The following description of sensor electronics associated with theelectronics unit is applicable to a variety of continuous analytesensors, such as non-invasive, minimally invasive, and/or invasive(e.g., transcutaneous and wholly implantable) sensors. For example, thesensor electronics and data processing as well as the receiverelectronics and data processing described below can be incorporated intothe wholly implantable glucose sensor disclosed in U.S. PatentPublication No. 2005-0245799-A1 and U.S. Patent Publication No.US-2006-0015020-A1. Additional description of sensor electronics can befound in co-pending U.S. patent application Ser. No. 11/734,184, filedon Apr. 11, 2007.

FIG. 4 is a block diagram that illustrates the electronics 132associated with the sensor system, in one embodiment. In thisembodiment, a potentiostat 134 is shown, which is operably connected toan electrode system (such as described above) and provides a voltage tothe electrodes, which biases the sensor to enable measurement of ancurrent signal indicative of the analyte concentration in the host (alsoreferred to as the analog portion). In some embodiments, thepotentiostat includes a resistor (not shown) that translates the currentinto voltage. In some alternative embodiments, a current to frequencyconverter is provided that is configured to continuously integrate themeasured current, for example, using a charge counting device.

An A/D converter 136 digitizes the analog signal into a digital signal,also referred to as “counts” for processing. Accordingly, the resultingraw data stream in counts, also referred to as raw sensor data, isdirectly related to the current measured by the potentiostat 134.

A processor module 138 includes the central control unit that controlsthe processing of the sensor electronics 132. In some embodiments, theprocessor module includes a microprocessor, however a computer systemother than a microprocessor can be used to process data as describedherein, for example an ASIC can be used for some or all of the sensor'scentral processing. The processor typically provides semi-permanentstorage of data, for example, storing data such as sensor identifier(ID) and programming to process data streams (for example, programmingfor data smoothing and/or replacement of signal artifacts such as isdescribed in U.S. Patent Publication No. US-2005-0043598-A1. Theprocessor additionally can be used for the system's cache memory, forexample for temporarily storing recent sensor data. In some embodiments,the processor module comprises memory storage components such as ROM,RAM, dynamic-RAM, static-RAM, non-static RAM, EEPROM, rewritable ROMs,flash memory, or the like.

In some embodiments, the processor module comprises a digital filter,for example, an infinite impulse response (IIR) or finite impulseresponse (FIR) filter, configured to smooth the raw data stream from theA/D converter. Generally, digital filters are programmed to filter datasampled at a predetermined time interval (also referred to as a samplerate). In some embodiments, wherein the potentiostat is configured tomeasure the analyte at discrete time intervals, these time intervalsdetermine the sample rate of the digital filter. In some alternativeembodiments, wherein the potentiostat is configured to continuouslymeasure the analyte, for example, using a current-to-frequency converteras described above, the processor module can be programmed to request adigital value from the A/D converter at a predetermined time interval,also referred to as the acquisition time. In these alternativeembodiments, the values obtained by the processor are advantageouslyaveraged over the acquisition time due the continuity of the currentmeasurement. Accordingly, the acquisition time determines the samplerate of the digital filter. In preferred embodiments, the processormodule is configured with a programmable acquisition time, namely, thepredetermined time interval for requesting the digital value from theA/D converter is programmable by a user within the digital circuitry ofthe processor module. An acquisition time of from about 2 seconds toabout 512 seconds is preferred; however any acquisition time can beprogrammed into the processor module. A programmable acquisition time isadvantageous in improving noise filtration, time lag, andprocessing/battery power.

Preferably, the processor module is configured to build the data packetfor transmission to an outside source, for example, an RF transmissionto a receiver as described in more detail below. Generally, the datapacket comprises a plurality of bits that can include a sensor ID code,raw data, filtered data, and/or error detection or correction. Theprocessor module can be configured to transmit any combination of rawand/or filtered data.

In some embodiments, the processor module further comprises atransmitter portion that determines the transmission interval of thesensor data to a receiver, or the like. In some embodiments, thetransmitter portion, which determines the interval of transmission, isconfigured to be programmable. In one such embodiment, a coefficient canbe chosen (e.g., a number of from about 1 to about 100, or more),wherein the coefficient is multiplied by the acquisition time (orsampling rate), such as described above, to define the transmissioninterval of the data packet. Thus, in some embodiments, the transmissioninterval is programmable from about 2 seconds to about 850 minutes, morepreferably from about 30 second to 5 minutes; however, any transmissioninterval can be programmable or programmed into the processor module.However, a variety of alternative systems and methods for providing aprogrammable transmission interval can also be employed. By providing aprogrammable transmission interval, data transmission can be customizedto meet a variety of design criteria (e.g., reduced battery consumption,timeliness of reporting sensor values, etc.)

Conventional glucose sensors measure current in the nanoAmp range. Incontrast to conventional glucose sensors, the preferred embodiments areconfigured to measure the current flow in the picoAmp range, and in someembodiments, femtoAmps. Namely, for every unit (mg/dL) of glucosemeasured, at least one picoAmp of current is measured. In someembodiments, from about 1, 2, 3, 4, or 5 picoAmps to about 25, 50, 100,250, or 500 picoAmps of current is measured for every unit (mg/dl) ofglucose measured. Preferably, the analog portion of the A/D converter136 is configured to continuously measure the current flowing at theworking electrode and to convert the current measurement to digitalvalues representative of the current. In one embodiment, the currentflow is measured by a charge counting device (e.g., a capacitor). Thus,a signal is provided, whereby a high sensitivity maximizes the signalreceived by a minimal amount of measured hydrogen peroxide (e.g.,minimal glucose requirements without sacrificing accuracy even in lowglucose ranges), reducing the sensitivity to oxygen limitations in vivo(e.g., in oxygen-dependent glucose sensors).

A battery 144 is operably connected to the sensor electronics 132 andprovides the power for the sensor. In one embodiment, the battery is alithium manganese dioxide battery; however, any appropriately sized andpowered battery can be used (for example, AAA, nickel-cadmium,zinc-carbon, alkaline, lithium, nickel-metal hydride, lithium-ion,zinc-air, zinc-mercury oxide, silver-zinc, and/or hermetically-sealed).In some embodiments, the battery is rechargeable, and/or a plurality ofbatteries can be used to power the system. The sensor can betranscutaneously powered via an inductive coupling, for example. In someembodiments, a quartz crystal 146 is operably connected to the processor138 and maintains system time for the computer system as a whole, forexample for the programmable acquisition time within the processormodule.

Optional temperature probe 140 is shown, wherein the temperature probeis located on the electronics assembly or the glucose sensor itself. Thetemperature probe can be used to measure ambient temperature in thevicinity of the glucose sensor. This temperature measurement can be usedto add temperature compensation to the calculated glucose value.

An RF module 148 is operably connected to the processor 138 andtransmits the sensor data from the sensor to a receiver within awireless transmission 150 via antenna 152. In some embodiments, a secondquartz crystal 154 provides the time base for the RF carrier frequencyused for data transmissions from the RF transceiver. In some alternativeembodiments, however, other mechanisms, such as optical, infraredradiation (IR), ultrasonic, or the like, can be used to transmit and/orreceive data.

In the RF telemetry module of the preferred embodiments, the hardwareand software are designed for low power requirements to increase thelongevity of the device (for example, to enable a life of from about 3to about 24 months, or more) with maximum RF transmittance from the invivo environment to the ex vivo environment for wholly implantablesensors (for example, a distance of from about one to ten meters ormore). Preferably, a high frequency carrier signal of from about 402 MHzto about 433 MHz is employed in order to maintain lower powerrequirements. Additionally, in wholly implantable devices, the carrierfrequency is adapted for physiological attenuation levels, which isaccomplished by tuning the RF module in a simulated in vivo environmentto ensure RF functionality after implantation; accordingly, thepreferred glucose sensor can sustain sensor function for 3 months, 6months, 12 months, or 24 months or more.

Preferably, the electronics unit indicates to the receiver (FIG. 5) thatcalibration is to be initialized (or re-initialized). The electronicsunit transmits a series of bits within a transmitted data packet whereina sensor code can be included in the periodic transmission of thedevice. The status code is used to communicate sensor status to thereceiving device. The status code can be inserted into any location inthe transmitted data packet, with or without other sensor information.In one embodiment, the status code is designed to be unique or nearunique to an individual sensor, which can be accomplished using a valuethat increments, decrements, or changes in some way after thetransmitter detects that a sensor has been removed and/or attached tothe transmitter. In an alternative embodiment, the status code can beconfigured to follow a specific progression, such as a BCDinterpretation of a Gray code.

In some embodiments, the sensor electronics 132 are configured to detecta current drop to zero in the working electrode 38 associated withremoval of a sensor 34 from the host, which can be configured to triggeran increment of the status code. If the incremented value reaches amaximum, it can be designed to roll over to 0. In some embodiments, thesensor electronics are configured to detect a voltage change cycleassociated with removal and/or re-insertion of the sensor, which can besensed in the counter electrode (e.g., of a three-electrode sensor),which can be configured to trigger an increment of the status code.

In some embodiments, the sensor electronics 132 can be configured tosend a special value (for example, 0) that indicates that theelectronics unit is not attached when removal of the sensor (orelectronics unit) is detected. This special value can be used to triggera variety of events, for example, to halt display of analyte values.Incrementing or decrementing routines can be used to skip this specialvalue.

In some embodiments, the electronics unit is configured to includeadditional contacts, which are designed to sense a specific resistance,or passive value, in the sensor system while the electronics unit isattached to the mounting unit. Preferably, these additional contacts areconfigured to detect information about a sensor, for example, whetherthe sensor is operatively connected to the mounting unit, the sensor'sID, a calibration code, or the like. For example, subsequent to sensingthe passive value, the sensor electronics can be configured to changethe sensor ID code by either mapping the value to a specific code, orinternally detecting that the code is different and adjusting the sensorID code in a predictable manner. As another example, the passive valuecan include information on parameters specific to a sensor (such as invitro sensitivity information as described elsewhere herein).

In some situations, it can be desirable to wait an amount of time afterinsertion of the sensor to allow the sensor to equilibrate in vivo, alsoreferred to as “break-in.” Accordingly, the sensor electronics can beconfigured to aid in decreasing the break-in time of the sensor byapplying different voltage settings (for example, starting with a highervoltage setting and then reducing the voltage setting) to speed theequilibration process.

In some situations, the sensor may not properly deploy, connect to, orotherwise operate as intended. Accordingly, the sensor electronics canbe configured such that if the current obtained from the workingelectrode, or the subsequent conversion of the current into digitalcounts, for example, is outside of an acceptable threshold, then thesensor is marked with an error flag, or the like. The error flag can betransmitted to the receiver to instruct the user to reinsert a newsensor, or to implement some other error correction.

The above-described detection and transmission methods can beadvantageously employed to minimize or eliminate human interaction withthe sensor, thereby minimizing human error and/or inconvenience.Additionally, the sensors of preferred embodiments do not require thatthe receiver be in proximity to the transmitter during sensor insertion.Any one or more of the above described methods of detecting andtransmitting insertion of a sensor and/or electronics unit can becombined or modified, as is appreciated by one skilled in the art.

Receiver

FIG. 5 is a perspective view of a receiver 158, in one embodiment.Preferably the electronics unit is wirelessly connected to a receiver158 via one- or two-way RF transmissions or the like. However, a wiredconnection is also contemplated. The receiver 158 provides much of theprocessing and display of the sensor data, and can be selectively wornand/or removed at the host's convenience. Thus, the sensor system can bediscreetly worn, and the receiver, which provides much of the processingand display of the sensor data, can be selectively worn and/or removedat the host's convenience. Particularly, the receiver 158 includesprogramming for retrospectively and/or prospectively initiating acalibration, converting sensor data, updating the calibration,evaluating received reference and sensor data, and evaluating thecalibration for the analyte sensor, such as described in more detailwith reference to U.S. Patent Publication No. US-2005-0027463-A1 andco-pending U.S. patent application Ser. No. 11/734,184 filed on Apr. 11,2007.

FIG. 6 is a block diagram that illustrates the configuration of themedical device in one embodiment, including a continuous analyte sensor,a receiver 158, and an optional external device 180. In general, theanalyte sensor system is any sensor configuration that provides anoutput signal indicative of a concentration of an analyte (e.g.,invasive, minimally-invasive, and/or non-invasive sensors as describedabove). The output signal is sent to a receiver 158 and received by aninput module 174, which is described in more detail below. The outputsignal is typically a raw data stream that is used to provide a usefulvalue of the measured analyte concentration to a patient or a doctor,for example. In some embodiments, the raw data stream can becontinuously or periodically algorithmically smoothed or otherwisemodified to diminish outlying points that do not accurately representthe analyte concentration, for example due to signal noise or othersignal artifacts, such as described in U.S. Pat. No. 6,931,327.

Referring again to FIG. 6, the receiver 158, which is operatively linkedto the sensor system 10, receives a data stream from the sensor system10 via the input module 174. In one embodiment, the input moduleincludes a quartz crystal operably connected to an RF transceiver (notshown) that together function to receive and synchronize data streamsfrom the sensor system 10. However, the input module 174 can beconfigured in any manner that is capable of receiving data from thesensor. Once received, the input module 174 sends the data stream to aprocessor 176 that processes the data stream, such as is described inmore detail below.

The processor 176 is the central control unit that performs theprocessing, such as storing data, analyzing data streams, calibratinganalyte sensor data, estimating analyte values, comparing estimatedanalyte values with time corresponding measured analyte values,analyzing a variation of estimated analyte values, downloading data, andcontrolling the user interface by providing analyte values, prompts,messages, warnings, alarms, or the like. The processor includes hardwareand software that performs the processing described herein, for exampleflash memory provides permanent or semi-permanent storage of data,storing data such as sensor ID, receiver ID, and programming to processdata streams (for example, programming for performing estimation andother algorithms described elsewhere herein) and random access memory(RAM) stores the system's cache memory and is helpful in dataprocessing.

Preferably, the input module 174 or processor module 176 performs aCyclic Redundancy Check (CRC) to verify data integrity, with or withouta method of recovering the data if there is an error. In someembodiments, error correction techniques such as those that use Hammingcodes or Reed-Solomon encoding/decoding methods are employed to correctfor errors in the data stream. In one alternative embodiment, aniterative decoding technique is employed, wherein the decoding isprocessed iteratively (e.g., in a closed loop) to determine the mostlikely decoded signal. This type of decoding can allow for recovery of asignal that is as low as 0.5 dB above the noise floor, which is incontrast to conventional non-iterative decoding techniques (such asReed-Solomon), which requires approximately 3 dB or about twice thesignal power to recover the same signal (e.g., a turbo code).

An output module 178, which is integral with and/or operativelyconnected with the processor 176, includes programming for generatingoutput based on the data stream received from the sensor system 10 andits processing incurred in the processor 176. In some embodiments,output is generated via a user interface 160.

The user interface 160 comprises a keyboard 162, speaker 164, vibrator166, backlight 168, liquid crystal display (LCD) screen 170, and one ormore buttons 172. The components that comprise the user interface 160include controls to allow interaction of the user with the receiver. Thekeyboard 162 can allow, for example, input of user information abouthimself/herself, such as mealtime, exercise, insulin administration,customized therapy recommendations, and reference analyte values. Thespeaker 164 can produce, for example, audible signals or alerts forconditions such as present and/or estimated (e.g., predicted)hyperglycemic or hypoglycemic conditions in a person with diabetes. Thevibrator 166 can provide, for example, tactile signals or alerts forreasons such as described with reference to the speaker, above. Thebacklight 168 can be provided, for example, to aid the user in readingthe LCD 170 in low light conditions. The LCD 170 can be provided, forexample, to provide the user with visual data output, such as isdescribed in U.S. Patent Publication No. US-2005-0203360-A1. FIGS. 17Bto 17D illustrate some additional visual displays that can be providedon the screen 170. In some embodiments, the LCD is a touch-activatedscreen, enabling each selection by a user, for example, from a menu onthe screen. The buttons 172 can provide for toggle, menu selection,option selection, mode selection, and reset, for example. In somealternative embodiments, a microphone can be provided to allow forvoice-activated control.

In some embodiments, prompts or messages can be displayed on the userinterface to convey information to the user, such as reference outliervalues, requests for reference analyte values, therapy recommendations,deviation of the measured analyte values from the estimated analytevalues, or the like. Additionally, prompts can be displayed to guide theuser through calibration or trouble-shooting of the calibration.

Additionally, data output from the output module 178 can provide wiredor wireless, one- or two-way communication between the receiver 158 andan optional external device 180. The external device 180 can be anydevice that wherein interfaces or communicates with the receiver 158. Insome embodiments, the external device 180 is a computer, and thereceiver 158 is able to download historical data for retrospectiveanalysis by the patient or physician, for example. In some embodiments,the external device 180 is a modem or other telecommunications station,and the receiver 158 is able to send alerts, warnings, emergencymessages, or the like, via telecommunication lines to another party,such as a doctor or family member. In some embodiments, the externaldevice 180 is an insulin pen, and the receiver 158 is able tocommunicate therapy recommendations, such as insulin amount and time tothe insulin pen. In some embodiments, the external device 180 is aninsulin pump, and the receiver 158 is able to communicate therapyrecommendations, such as insulin amount and time to the insulin pump.The external device 180 can include other technology or medical devices,for example pacemakers, implanted analyte sensor patches, other infusiondevices, telemetry devices, or the like.

The user interface 160, including keyboard 162, buttons 172, amicrophone (not shown), and the external device 180, can be configuredto allow input of data. Data input can be helpful in obtaininginformation about the patient (for example, meal time, exercise, or thelike), receiving instructions from a physician (for example, customizedtherapy recommendations, targets, or the like), and downloading softwareupdates, for example. Keyboard, buttons, touch-screen, and microphoneare all examples of mechanisms by which a user can input data directlyinto the receiver. A server, personal computer, personal digitalassistant, insulin pump, and insulin pen are examples of externaldevices that can provide useful information to the receiver. Otherdevices internal or external to the sensor that measure other aspects ofa patient's body (for example, temperature sensor, accelerometer, heartrate monitor, oxygen monitor, or the like) can be used to provide inputhelpful in data processing. In one embodiment, the user interface canprompt the patient to select an activity most closely related to theirpresent activity, which can be helpful in linking to an individual'sphysiological patterns, or other data processing. In another embodiment,a temperature sensor and/or heart rate monitor can provide informationhelpful in linking activity, metabolism, and glucose excursions of anindividual. While a few examples of data input have been provided here,a variety of information can be input, which can be helpful in dataprocessing.

Algorithms

FIG. 7 provides a flow chart 200 that illustrates the initialcalibration and data output of the sensor data in one embodiment,wherein calibration is responsive to reference analyte data. Initialcalibration, also referred to as start-up mode, occurs at theinitialization of a sensor, for example, the first time an electronicsunit is used with a particular sensor. In certain embodiments, start-upcalibration is triggered when the system determines that it can nolonger remain in normal or suspended mode, which is described in moredetail in co-pending U.S. patent application Ser. No. 11/734,184 filedon Apr. 11, 2007.

Calibration of an analyte sensor comprises data processing that convertssensor data signal into an estimated analyte measurement that ismeaningful to a user. Accordingly, a reference analyte value is used tocalibrate the data signal from the analyte sensor.

At block 202, a sensor data receiving module, also referred to as thesensor data module, receives sensor data (e.g., a data stream),including one or more time-spaced sensor data points, from the sensor 34via the receiver 158, which can be in wired or wireless communicationwith the sensor. The sensor data point(s) can be smoothed (filtered) incertain embodiments using a filter, for example, a finite impulseresponse (FIR) or infinite impulse response (IIR) filter. During theinitialization of the sensor, prior to initial calibration, the receiverreceives and stores the sensor data, however it can be configured to notdisplay any data to the user until initial calibration and, optionally,stabilization of the sensor has been established. In some embodiments,the data stream can be evaluated to determine sensor break-in(equilibration of the sensor in vitro or in vivo).

At block 204, a reference data receiving module, also referred to as thereference input module, receives reference data from a reference analytemonitor, including one or more reference data points. In one embodiment,the reference analyte points can comprise results from a self-monitoredblood analyte test (e.g., finger stick test). For example, the user canadminister a self-monitored blood analyte test to obtain an analytevalue (e.g., point) using any known analyte sensor, and then enter thenumeric analyte value into the computer system. Alternatively, aself-monitored blood analyte test is transferred into the computersystem through a wired or wireless connection to the receiver (e.g.computer system) so that the user simply initiates a connection betweenthe two devices, and the reference analyte data is passed or downloadedbetween the self-monitored blood analyte test and the receiver.

In yet another embodiment, the self-monitored analyte monitor (e.g.,SMBG) is integral with the receiver so that the user simply provides ablood sample to the receiver, and the receiver runs the analyte test todetermine a reference analyte value, such as is described in more detailherein and with reference to U.S. Patent Publication No.US-2005-0154271-A1, which is incorporated herein by reference in itsentirety and which describes some systems and methods for integrating areference analyte monitor into a receiver for a continuous analytesensor.

In some embodiments, the integrated receiver comprises a microprocessor,which can be programmed to process sensor data to perform thecalibration. Such programming, which can be stored in a computerreadable memory, can also comprise data acceptability testing usingcriteria such as that discussed above with reference to FIG. 7. Forexample the microprocessor can be programmed so as to determine the rateof change of glucose concentration based on the continuous sensor data,and perform calibration only if the rate of change is below apredetermined threshold, such as 2 mg/dL/min. In some embodiments thereceiver can also comprise modules to perform a calibration proceduresuch as is described herein. Such modules include, but are not limitedto an input module, a data matching module, a calibration module, aconversion function module, a sensor data transformation module, acalibration evaluation module, a clinical module, a stability module,and a user interface, each of which have been described herein.

The monitor can be of any suitable configuration. For example, in oneembodiment, the reference analyte points can comprise results from aself-monitored blood analyte test (e.g., from a finger stick test), suchas those described in U.S. Pat. Nos. 6,045,567; 6,156,051; 6,197,040;6,284,125; 6,413,410; and 6,733,655. In one such embodiment, the usercan administer a self-monitored blood analyte test to obtain an analytevalue (e.g., point) using any suitable analyte sensor, and then enterthe numeric analyte value into the computer system (e.g., the receiver).In another such embodiment, a self-monitored blood analyte testcomprises a wired or wireless connection to the receiver (e.g. computersystem) so that the user simply initiates a connection between the twodevices, and the reference analyte data is passed or downloaded betweenthe self-monitored blood analyte test and the receiver. In yet anothersuch embodiment, the self-monitored analyte test is integral with thereceiver so that the user simply provides a blood sample to thereceiver, and the receiver runs the analyte test to determine areference analyte value.

Other suitable monitor configurations include, for example, thosedescribed in U.S. Pat. Nos. 4,994,167, 4,757,022, and 6,551,494. Inalternative embodiments, the single point glucose monitor of thisparticular embodiment can be configured as described with reference toU.S. Patent Publication No. US-2005-0154271-A1. In other alternativeembodiments, the monitor can be configured using other glucose meterconfigurations. Numerous advantages associated with the integratedreceiver, such as ensuring accurate time stamping of the single pointglucose test at the receiver and other advantages described herein, canbe provided by an integrated continuous glucose receiver and singlepoint glucose monitor, such as described herein.

In some embodiments, the reference data is based on sensor data fromanother substantially continuous analyte sensor, e.g., a transcutaneousanalyte sensor described herein, or another type of suitable continuousanalyte sensor. In an embodiment employing a series of two or moretranscutaneous (or other continuous) sensors, the sensors can beemployed so that they provide sensor data in discrete or overlappingperiods. In such embodiments, the sensor data from one continuous sensorcan be used to calibrate another continuous sensor, or be used toconfirm the validity of a subsequently employed continuous sensor.

In some embodiments, reference data can be subjected to “outlierdetection” wherein the accuracy of a received reference analyte data isevaluated as compared to time-corresponding sensor data. In oneembodiment, the reference data is compared to the sensor data on amodified Clarke Error Grid (e.g., a test similar to the Clarke ErrorGrid except the boundaries between the different regions are modifiedslightly) to determine if the data falls within a predeterminedthreshold. If the data is not within the predetermined threshold, thenthe receiver can be configured to request additional reference analytedata. If the additional reference analyte data confirms (e.g., closelycorrelates to) the first reference analyte data, then the first andsecond reference values are assumed to be accurate and calibration ofthe sensor is adjusted or re-initialized. Alternatively, if the secondreference analyte value falls within the predetermined threshold, thenthe first reference analyte value is assumed to be an outlier and thesecond reference analyte value is used by the algorithm(s) instead. Inone alternative embodiments of outlier detection, projection is used toestimate an expected analyte value, which is compared with the actualvalue and a delta evaluated for substantial correspondence. However,other methods of outlier detection are possible.

Certain acceptability parameters can be set for reference valuesreceived from the user. In some embodiments, the calibration processmonitors the continuous analyte sensor data stream to determine apreferred time for capturing reference analyte concentration values forcalibration of the continuous sensor data stream. In an example whereinthe analyte sensor is a continuous glucose sensor, when data (forexample, observed from the data stream) changes too rapidly, thereference glucose value may not be sufficiently reliable for calibrationdue to unstable glucose changes in the host. In contrast, when sensorglucose data are relatively stable (for example, relatively low rate ofchange), a reference glucose value can be taken for a reliablecalibration. For example, in one embodiment, the receiver can beconfigured to only accept reference analyte values of from about 40mg/dL to about 400 mg/dL. As another example, the receiver can beconfigured to only accept reference analyte values when the rate ofchange is less than a predetermined maximum, such as 1, 1.5, 2, 2.5, 3,or 3.5, mg/dL/min. As yet another example, the receiver can beconfigured to only accept reference analyte values when the rate ofacceleration (or deceleration) is less than a predetermined maximum,such as 0.01 mg/dL/min², 0.02 mg/dL/min², 0.03 mg/dL/min², 0.04mg/dL/min², or 0.05 mg/dL/min² or more.

In some embodiments, the reference data is pre-screened according toenvironmental and/or physiological issues, such as time of day, oxygenconcentration, postural effects, and patient-entered environmental data.In one example embodiment, wherein the sensor comprises an implantableglucose sensor, an oxygen sensor within the glucose sensor is used todetermine if sufficient oxygen is being provided to successfullycomplete the necessary enzyme and electrochemical reactions for glucosesensing. In another example wherein the sensor comprises an implantableglucose sensor, the counter electrode could be monitored for a“rail-effect,” that is, when insufficient oxygen is provided at thecounter electrode causing the counter electrode to reach operational(e.g., circuitry) limits. In some embodiments the receiver is configuredsuch that when conditions for accepting reference analyte values are notmet, the user is notified. Such notice can include an indication as tothe cause of the unacceptability, such as low oxygen or high rate ofanalyte value change. In some embodiments the indication can alsoinclude an indication of suggested corrective action, such as moderatelyincreasing muscular activity so as to increase oxygen levels or to waituntil the rate of analyte value change reduces to an acceptable value.

In one embodiment, the calibration process can prompt the user via theuser interface to “calibrate now” when the reference analyte values areconsidered acceptable. In some embodiments, the calibration process canprompt the user via the user interface to obtain a reference analytevalue for calibration at intervals, for example when analyteconcentrations are at high and/or low values. In some additionalembodiments, the user interface can prompt the user to obtain areference analyte value for calibration based at least in part uponcertain events, such as meals, exercise, large excursions in analytelevels, faulty or interrupted data readings, or the like. In someembodiments, the algorithms can provide information useful indetermining when to request a reference analyte value. For example, whenanalyte values indicate approaching clinical risk, the user interfacecan prompt the user to obtain a reference analyte value.

In yet another example embodiment, the patient is prompted to enter datainto the user interface, such as meal times and/or amount of exercise,which can be used to determine likelihood of acceptable reference data.Evaluation data, such as described in the paragraphs above, can be usedto evaluate a preferred time for reference analyte measurement.Correspondingly, the user interface can then prompt the user to providea reference data point for calibration within a given time period.Consequently, because the receiver proactively prompts the user duringpreferred calibration times, the likelihood of error due toenvironmental and physiological limitations may decrease and consistencyand acceptability of the calibration may increase.

In some embodiments, the calibration process monitors the continuousanalyte sensor data stream to determine a preferred time for capturingreference analyte concentration values for calibration of the continuoussensor data stream. In an example wherein the analyte sensor is acontinuous glucose sensor, when data (for example, observed from thedata stream) changes too rapidly, the reference glucose value may not besufficiently reliable for calibration due to unstable glucose changes inthe host. In contrast, when sensor glucose data are relatively stable(for example, relatively low rate of change), a reference glucose valuecan be taken for a reliable calibration. In one embodiment, thecalibration process can prompt the user via the user interface to“calibrate now” when the analyte sensor is considered stable.

Referring again to FIG. 7, at block 206, a data matching module, alsoreferred to as the processor module, matches reference data (e.g., oneor more reference analyte data points) with substantially timecorresponding sensor data (e.g., one or more sensor data points) toprovide one or more matched data pairs. One reference data point can bematched to one time corresponding sensor data point to form a matcheddata pair. Alternatively, a plurality of reference data points can beaveraged (e.g., equally or non-equally weighted average, mean-value,median, or the like) and matched to one time corresponding sensor datapoint to form a matched data pair, one reference data point can bematched to a plurality of time corresponding sensor data points averagedto form a matched data pair, or a plurality of reference data points canbe averaged and matched to a plurality of time corresponding sensor datapoints averaged to form a matched data pair.

In one embodiment, time corresponding sensor data comprises one or moresensor data points that occur from about 0 minutes to about 20 minutesafter the reference analyte data time stamp (e.g., the time that thereference analyte data is obtained). In one embodiment, a 5 minute timedelay is chosen to compensate for a system time-lag (e.g., the timenecessary for the analyte to diffusion through a membrane(s) of ananalyte sensor). In alternative embodiments, the time correspondingsensor value can be greater than or less than that of theabove-described embodiment, for example ±60 minutes. Variability in timecorrespondence of sensor and reference data can be attributed to, forexample, a longer or shorter time delay introduced by the data smoothingfilter, or if the configuration of the analyte sensor incurs a greateror lesser physiological time lag.

In some implementations of the sensor, the reference analyte data isobtained at a time that is different from the time that the data isinput into the receiver. Accordingly, the “time stamp” of the referenceanalyte (e.g., the time at which the reference analyte value wasobtained) is not the same as the time at which the receiver obtained thereference analyte data. Therefore, some embodiments include a time stamprequirement that ensures that the receiver stores the accurate timestamp for each reference analyte value, that is, the time at which thereference value was actually obtained from the user.

In certain embodiments, tests are used to evaluate the best-matched pairusing a reference data point against individual sensor values over apredetermined time period (e.g., about 30 minutes). In one suchembodiment, the reference data point is matched with sensor data pointsat 5 minute intervals and each matched pair is evaluated. The matchedpair with the best correlation can be selected as the matched pair fordata processing. In some alternative embodiments, matching a referencedata point with an average of a plurality of sensor data points over apredetermined time period can be used to form a matched pair.

In certain embodiments, the data matching module only forms matchedpairs when a certain analyte value condition is satisfied. Such acondition can include any of the conditions discussed above withreference to embodiments pre-screening or conditionally acceptingreference analyte value data at block 204.

At block 208, a calibration set module, also referred to as thecalibration module or processor module, forms an initial calibration setfrom a set of one or more matched data pairs, which are used todetermine the relationship between the reference analyte data and thesensor analyte data. The matched data pairs, which make up the initialcalibration set, can be selected according to predetermined criteria.The criteria for the initial calibration set can be the same as, ordifferent from, the criteria for the updated calibration sets. Incertain embodiments, the number (n) of data pair(s) selected for theinitial calibration set is one. In other embodiments, n data pairs areselected for the initial calibration set wherein n is a function of thefrequency of the received reference data points. In various embodiments,two data pairs make up the initial calibration set or six data pairsmake up the initial calibration set. In an embodiment wherein asubstantially continuous analyte sensor provides reference data,numerous data points are used to provide reference data from more than 6data pairs (e.g., dozens or even hundreds of data pairs). In oneexemplary embodiment, a substantially continuous analyte sensor provides288 reference data points per day (every five minutes for twenty-fourhours), thereby providing an opportunity for a matched data pair 288times per day, for example. While specific numbers of matched data pairsare referred to in the preferred embodiments, any suitable number ofmatched data pairs per a given time period can be employed.

In certain embodiments, the data pairs are selected only when a certainanalyte value condition is satisfied. Such a condition can include anyof the conditions discussed above with reference to embodimentspre-screening or conditionally accepting reference analyte value data atblock 204. In certain embodiments, the data pairs that form the initialcalibration set are selected according to their time stamp, for example,by waiting a predetermined “break-in” time period after implantation,the stability of the sensor data can be increased. In certainembodiments, the data pairs that form the initial calibration set arespread out over a predetermined time period, for example, a period oftwo hours or more. In certain embodiments, the data pairs that form theinitial calibration set are spread out over a predetermined glucoserange, for example, spread out over a range of at least 90 mg/dL ormore.

At block 210, a conversion function module, also referred to as theconversion module or processor module, uses the calibration set tocreate a conversion function. The conversion function substantiallydefines the relationship between the reference analyte data and theanalyte sensor data.

A variety of known methods can be used with the preferred embodiments tocreate the conversion function from the calibration set. In oneembodiment, wherein a plurality of matched data points form thecalibration set, a linear least squares regression is used to calculatethe conversion function; for example, this regression calculates a slopeand an offset using the equation y=mx+b. A variety of regression orother conversion schemes can be implemented herein.

In certain embodiments, the conversion function module only creates aconversion function when a certain analyte value condition is satisfied.Such a condition can include any of the conditions discussed above withreference to embodiments pre-screening or conditionally acceptingreference analyte value data at block 204 or with reference to selectingdata pairs at block 208.

In some alternative embodiments, the sensor is calibrated with asingle-point through the use of a dual-electrode system to simplifysensor calibration. In one such dual-electrode system, a first electrodefunctions as a hydrogen peroxide sensor including a membrane systemcontaining glucose-oxidase disposed thereon, which operates as describedherein. A second electrode is a hydrogen peroxide sensor that isconfigured similar to the first electrode, but with a modified membranesystem (with the enzyme domain removed, for example). This secondelectrode provides a signal composed mostly of the baseline signal, b.

In some dual-electrode systems, the baseline signal is (electronicallyor digitally) subtracted from the glucose signal to obtain a glucosesignal substantially without baseline. Accordingly, calibration of theresultant difference signal can be performed by solving the equationy=mx+b with a single paired measurement. Calibration of the implantedsensor in this alternative embodiment can be made less dependent on thevalues/range of the paired measurements, less sensitive to error inmanual blood glucose measurements, and can facilitate the sensor's useas a primary source of glucose information for the user. U.S. PatentPublication No. US-2005-0143635-A1 describes systems and methods forsubtracting the baseline from a sensor signal.

In some alternative dual-electrode system embodiments, the analytesensor is configured to transmit signals obtained from each electrodeseparately (e.g., without subtraction of the baseline signal). In thisway, the receiver can process these signals to determine additionalinformation about the sensor and/or analyte concentration. For example,by comparing the signals from the first and second electrodes, changesin baseline and/or sensitivity can be detected and/or measured and usedto update calibration (e.g., without the use of a reference analytevalue). In one such example, by monitoring the corresponding first andsecond signals over time, an amount of signal contributed by baselinecan be measured. In another such example, by comparing fluctuations inthe correlating signals over time, changes in sensitivity can bedetected and/or measured.

In some alternative embodiments, a regression equation y=mx+b is used tocalculate the conversion function; however, prior information can beprovided for m and/or b, thereby enabling calibration to occur withfewer paired measurements. In one calibration technique, priorinformation (e.g., obtained from in vivo or in vitro tests) determines asensitivity of the sensor and/or the baseline signal of the sensor byanalyzing sensor data from measurements taken by the sensor (e.g., priorto inserting the sensor). For example, if there exists a predictiverelationship between in vitro sensor parameters and in vivo parameters,then this information can be used by the calibration procedure. Forexample, if a predictive relationship exists between in vitrosensitivity and in vivo sensitivity, m≈f(m_(in vitro)), then thepredicted m can be used, along with a single matched pair, to solve forb (b=y−mx). If, in addition, b can be assumed=0, for example with adual-electrode configuration that enables subtraction of the baselinefrom the signal such as described above, then both m and b are known apriori, matched pairs are not needed for calibration, and the sensor canbe completely calibrated e.g. without the need for reference analytevalues (e.g. values obtained after implantation in vivo.)

In another alternative embodiment, prior information can be provided toguide or validate the baseline (b) and/or sensitivity (m) determinedfrom the regression analysis. In this embodiment, boundaries can be setfor the regression line that defines the conversion function such thatworking sensors are calibrated accurately and easily (with two points),and non-working sensors are prevented from being calibrated. If theboundaries are drawn too tightly, a working sensor may not enter intocalibration. Likewise, if the boundaries are drawn too loosely, thescheme can result in inaccurate calibration or can permit non-workingsensors to enter into calibration. For example, subsequent to performingregression, the resulting slope and/or baseline are tested to determinewhether they fall within a predetermined acceptable threshold(boundaries). These predetermined acceptable boundaries can be obtainedfrom in vivo or in vitro tests (e.g., by a retrospective analysis ofsensor sensitivities and/or baselines collected from a set ofsensors/patients, assuming that the set is representative of futuredata).

If the slope and/or baseline fall within the predetermined acceptableboundaries, then the regression is considered acceptable and processingcontinues to the next step (e.g., block 212). Alternatively, if theslope and/or baseline fall outside the predetermined acceptableboundaries, steps can be taken to either correct the regression orfail-safe such that a system will not process or display errant data.This can be useful in situations wherein regression results in errantslope or baseline values. For example, when points (matched pairs) usedfor regression are too close in value, the resulting regressionstatistically is less accurate than when the values are spread fartherapart. As another example, a sensor that is not properly deployed or isdamaged during deployment can yield a skewed or errant baseline signal.

In some alternative embodiments, the sensor system does not requireinitial and/or update calibration by the host; in these alternativeembodiments, also referred to as “zero-point calibration” embodiments,use of the sensor system without requiring a reference analytemeasurement for initial and/or update calibration is enabled. Ingeneral, the systems and methods of the preferred embodiments providefor stable and repeatable sensor manufacture, particularly when tightlycontrolled manufacturing processes are utilized. Namely, a batch ofsensors of the preferred embodiments can be designed with substantiallythe same baseline (b) and/or sensitivity (m) (+/−10%) when tested invitro. Additionally, the sensor of the preferred embodiments can bedesigned for repeatable m and b in vivo. Thus, an initial calibrationfactor (conversion function) can be programmed into the sensor (sensorelectronics and/or receiver electronics) that enables conversion of rawsensor data into calibrated sensor data solely using informationobtained prior to implantation (namely, initial calibration does notrequire a reference analyte value). Additionally, to obviate the needfor recalibration (update calibration) during the life of the sensor,the sensor is designed to minimize drift of the sensitivity and/orbaseline over time in vivo. Accordingly, the preferred embodiments canbe manufactured for zero point calibration.

At block 212, a sensor data transformation module, also referred to asthe calibration module, conversion module, or processor module, uses theconversion function to transform sensor data into substantiallyreal-time analyte value estimates, also referred to as calibrated data,or converted sensor data, as sensor data is continuously (orintermittently) received from the sensor. For example, the sensor data,which can be provided to the receiver in “counts,” is translated in toestimate analyte value(s) in mg/dL. In other words, the offset value atany given point in time can be subtracted from the raw value (e.g., incounts) and divided by the slope to obtain the estimate analyte value:

${{mg}\text{/}{dL}} = \frac{\left( {{rawvalue} - {offset}} \right)}{slope}$

In one embodiment, the conversion function can be used to estimateanalyte values for a future time period by forward projection. Inalternative preferred embodiments, the processor can provide intelligentestimation, including dynamic determination of an algorithm,physiological boundaries, evaluation of the estimative algorithm,analysis of variations associated with the estimation, and comparison ofmeasured analyte values with time corresponding estimated analytevalues.

In some alternative embodiments, the sensor and/or reference analytevalues are stored in a database for retrospective analysis.

In certain embodiments, the sensor data transformation module onlyconverts sensor data points into calibrated data points when a certainanalyte value condition is satisfied. Such a condition can include anyof the conditions discussed above with reference to embodimentspre-screening or conditionally accepting reference analyte value data atblock 204, with reference to selecting data pairs at block 208, or withreference to creating a conversion function at block 210.

At block 214, an output module provides output to the user via the userinterface. The output is representative of the estimated analyte value,which is determined by converting the sensor data into a meaningfulanalyte value. User output can be in the form of a numeric estimatedanalyte value, an indication of directional trend of analyteconcentration, and/or a graphical representation of the estimatedanalyte data over a period of time, for example. Other representationsof the estimated analyte values are also possible, for example audio andtactile.

In one exemplary embodiment, the estimated analyte value is representedby a numeric value. In other exemplary embodiments, the user interfacegraphically represents the estimated analyte data trend overpredetermined a time period (e.g., one, three, and nine hours,respectively). In alternative embodiments, other time periods can berepresented.

In some embodiments, the user interface begins displaying data to theuser after the sensor's stability has been affirmed. In some alternativeembodiments, however, the user interface displays data that is somewhatunstable (e.g., does not have sufficient stability and/or accuracy); inthese embodiments, the receiver may also include an indication ofinstability of the sensor data (e.g., flashing, faded, or anotherindication of sensor instability displayed on the user interface). Insome embodiments, the user interface informs the user of the status ofthe stability of the sensor data.

Accordingly, after initial calibration of the sensor, and optionallydetermination of stability of the sensor data, real-time continuousanalyte information can be displayed on the user interface so that theuser can regularly and proactively care for his/her diabetic conditionwithin the bounds set by his/her physician.

In alternative embodiments, the conversion function is used to predictanalyte values at future points in time. These predicted values can beused to alert the user of upcoming hypoglycemic or hyperglycemic events.Additionally, predicted values can be used to compensate for the timelag (e.g., 15 minute time lag such as described elsewhere herein), sothat an estimated analyte value displayed to the user represents theinstant time, rather than a time delayed estimated value.

In some embodiments, the substantially real time estimated analytevalue, a predicted future estimate analyte value, a rate of change,and/or a directional trend of the analyte concentration is used tocontrol the administration of a constituent to the user, including anappropriate amount and time, in order to control an aspect of the user'sbiological system. One such example is a closed loop glucose sensor andinsulin pump, wherein the analyte data (e.g., estimated glucose value,rate of change, and/or directional trend) from the glucose sensor isused to determine the amount of insulin, and time of administration,that may be given to a diabetic user to evade hyper- and hypoglycemicconditions.

In some embodiments, annotations are provided on the graph; for example,bitmap images are displayed thereon, which represent events experiencedby the host. For example, information about meals, insulin, exercise,sensor insertion, sleep, and the like, can be obtained by the receiver(by user input or receipt of a transmission from another device) anddisplayed on the graphical representation of the host's glucose overtime. It is believed that illustrating a host's life events matched witha host's glucose concentration over time can be helpful in educating thehost to his or her metabolic response to the various events.

In yet another alternative embodiment, the sensor utilizes one or moreadditional electrodes to measure an additional analyte. Suchmeasurements can provide a baseline or sensitivity measurement for usein calibrating the sensor. Furthermore, baseline and/or sensitivitymeasurements can be used to trigger events such as digital filtering ofdata or suspending display of data, all of which are described in moredetail in U.S. Patent Publication No. US-2005-0143635-A1.

Accordingly, after initial calibration of the sensor, continuous analytevalues can be displayed on the user interface so that the user canregularly and proactively care for his/her diabetic condition within thebounds set by his/her physician. Both the reference analyte data and thesensor analyte data from the continuous analyte sensor can be displayedto the user. In an embodiment wherein the continuous analyte sensorfunctions as an adjunctive device to a reference analyte monitor, theuser interface can display numeric reference analyte data, while showingthe sensor analyte data only in a graphical representation so that theuser can see the historical and present sensor trend information as wellas the most recent reference analyte data value. In an embodimentwherein the continuous analyte sensor functions as a non-adjunctivedevice to the reference analyte monitor, the user interface can displaythe reference analyte data and/or the sensor analyte data. The user cantoggle through menus and screens using the buttons in order to viewalternate data and/or screen formats, for example.

In some embodiments, the measured analyte value, an estimated futureanalyte value, a rate of change, and/or a directional trend of theanalyte concentration is used to control the administration of aconstituent to the user, including an appropriate amount and time, inorder to control an aspect of the user's biological system. One suchexample is a closed loop glucose sensor and insulin pump, wherein theglucose data (for example, estimated glucose value, rate of change,and/or directional trend) from the glucose sensor is used to determinethe amount of insulin, and time of administration, that can be given toa person with diabetes to evade hyperglycemic and hypoglycemicconditions.

Electronic Identification and Removal of Non-Constant Noise

In addition blocking and/or diluting interfering species before they cancause noise on the sensor signal, a non-constant noise signal componentcan be electronically identified, such that the identified noisecomponent can be removed from the signal by algorithmic/mathematicalmeans, in some embodiments. For example, in a glucose sensor (e.g., asdescribed herein) that catalyzes the conversion of oxygen and glucose tohydrogen peroxide and gluconate (e.g., by GOX incorporated into themembrane system), for each glucose molecule metabolized there is anequivalent change in molecular concentration in the co-reactant O₂ andthe product H₂O₂. Consequently, one can use an electrode (for example,working electrode 16) to monitor the concentration-induced currentchange in either the co-reactant or the product (for example, H₂O₂) todetermine glucose concentration. However, if an interfering speciesexists with an oxidation or reduction potential that overlaps with theco-reactant or the product (for example, H₂O₂), then the current changedoes not accurately reflect glucose concentration. Additionally, if anoxygen deficiency exists, such that insufficient oxygen is present toreact with an analyte at the enzyme for example, then the current changesimilarly does not accurately reflect glucose concentration.

It is noted that a glucose sensor signal obtained from glucose when thebias potential is set from about +0.35V to about +0.75V is substantiallyconstant under standard physiologic conditions. In contrast, a glucosesensor signal obtained from interfering species when the same biaspotentials are set (from about +0.35V to about +0.75V) is notsubstantially constant under standard physiologic conditions.Current-voltage curves are known for various analytes and are availablein the literature (for example, such as described by Lerner et al. Ann NY Acad Sci 1984, 428, 263-278). Additional description can be found inU.S. Pat. No. 7,081,195.

EXAMPLES Example 1

Resistance Domain Configurations to Increased the Analyte Signal ReduceNon-Constant Noise

Transcutaneous sensors, with electrode, interference, enzyme andresistance (polyurethane blend) domains, were built and tested innon-diabetic hosts. The control and test sensors were built as describedin U.S. Publication No. 2006-0020187, which is incorporated herein byreference in its entirety, with the following exception: the resistancedomain of the test sensors was formed of 3 layers of a 60% ChronoThane®H (CardioTech International, Wilmington, Mass., USA; the PEOconcentration of ChronoThane® H is about 25%) polyurethane blendsolution, as compared to a single layer of a 45% ChronoThane® Hpolyurethane blend solution in the control sensors. Test and controlsensors were implanted bilaterally in the abdomens of non-diabetic hostvolunteers, for a period of about 7 days.

FIG. 8 illustrates exemplary test results from one test sensor, over aperiod of about 7 days, after sensor break-in. The Y-axis representssignal intensity (in counts). The X-axis represents time. Double-headedarrows approximately indicate the days of the study. The total signaldetected by the test glucose sensor is shown as dotted line 1000. Todetermine the signal components, the total signal 1000 was analyzed inthe following manner. First, the total signal 1000 was filtered using anIIR filter to obtain the filtered signal 1020 . . . The non-constantnoise component 1010 was obtained by subtracting the filtered signal1020 from the total signal 1000. Next, the filtered signal 1020 wascalibrated using glucose values obtained from a finger-stick glucosemeter (SMBG), as described as described in more detail elsewhere herein,to obtain the constant noise signal component 1030 (e.g., from thebaseline of the calibration equation). Finally, the analyte component1040 (e.g., glucose concentration) of the total signal 1000 was obtainedby subtracting the constant noise signal component 1030 from thefiltered signal 1020.

During the seven days the sensor was tested, the glucose signal variedwidely, depending upon the host's activity and calorie consumption.Using the Root Mean Square (RMS) method, it was determined that thenon-constant noise signal component was no more than about 4.2% of thetotal signal during the 7 days of the trial. Additionally, during aboutdays two through five of the trial, the non-constant noise was no morethan about 2.9% of the total signal.

Accordingly, it was shown that the non-constant noise component can bereduced to less than about 20% of the total signal over a period ofabout 7 days by increasing the resistance domain thickness, as describedin more detail elsewhere herein.

Example 2

A Lubricious Coating Configured to Reduce Non-Constant Noise

Control and test sensors, with electrode, enzyme and resistance domains,were built as described in U.S. Patent Publication No.US-2006-0020187-A1, including a resistance domain formed using apolyurethane polymer blend having about 8 wt. % PEO, as described in thesection entitled “Polyurethane Polymer Material” above. A lubriciouscoating was applied to the test sensors by dipping them one time into asolution of HydroMed™ (CardioTech International, Inc., Wilmington,Mass., USA) and drying. The control and test sensors were tested invitro (see Table 1, below). The test sensors (with the lubriciouscoating) had a substantially increased sensitivity (m) but with nocorresponding increase in constant noise (b), when compared to controlsensors (no lubricious coating). Accordingly, it was shown thatapplication of a lubricious coating over a polyurethane blend resistancedomain of a glucose sensor can (in vitro) substantially increase theanalyte component of the total signal, while having little affect onconstant noise (e.g., baseline).

TABLE 1 Average Average Sensitivity Constant Sensor Type (pA/mg/dl)Noise Test (with lubricious coating) 20.68 1.36 Control (no lubriciouscoating) 8.33 1.36

FIG. 9 is a graph showing exemplary test results when a test sensor asdescribed above, including a lubricious coating, was implanted in anon-diabetic human host. Components of the Total Signal 1000 weredetermined, as described in Example 1. The Y-axis represents signalintensity (in counts). The X-axis represents time. FIG. 9 shows thenon-constant noise component 1010, the filtered signal 1020, theconstant noise component 1030 and the analyte signal 1040. Using the RMSmethod, it was determined that, for the test sensor including alubricious coating, the analyte component of the total signal was atleast about 96% for about four days, after sensor break-in.Additionally, the non-constant noise component was no more than about 5%for about four days, after sensor break-in. Accordingly, it was shownthat, in ambulatory humans, application of a lubricious coating to asensor over a resistance domain provides a sensor that, in vivo, has asubstantially non-constant non-analyte related signal component does notsubstantially contribute to the signal after sensor break-in.

Example 3

Discontinuous Hydrophilic Overcoat on Resistance Domain Configured toReduce Non-Constant Noise

To determine if a hydrophilic overcoat on the resistance layer canincrease the analyte signal component and/or reduce the non-constantnoise component, test and control sensors were build and tested involunteer human hosts, over a period of 3 days. Both the test andcontrol sensors included an electrode layer, an enzyme layer and apolyurethane blend resistance domain. The polyurethane blend used toform the resistance domain included 8% hydrophile (i.e., PEO). Afterfabrication, the test sensors were sprayed (one time) in a solution of5% ChronoThane® H (about 25% PEO; CardioTech International, Wilmington,Mass., USA) and cured. Test and control sensors were implantedbilaterally in the abdomens of the volunteer human hosts. FIG. 10 is agraph showing test results from one exemplary sensor. Components of theTotal Signal 1000 were determined, as described in Example 1. The Y-axisrepresents signal intensity (in counts). The X-axis represents time.FIG. 10 shows the non-constant noise component 1010, the filtered signal1020, the constant noise component 1030 and the analyte signal 1040.Using the RMS method, it was determined that, for sensor having ahydrophilic coating, the non-constant noise component of the totalsignal was no more than about 3% during the study.

While not wishing to be bound by theory, it is believed that applicationof a hydrophilic overcoat to the sensor can provide a sensor that has anon-constant noise component that is less than about 20% of the totalsignal.

Methods and devices that are suitable for use in conjunction withaspects of the preferred embodiments are disclosed in U.S. Pat. Nos.4,994,167; 4,757,022; 6,001,067; 6,741,877; 6,702,857; 6,558,321;6,931,327; 6,862,465; 7,074,307; 7,081,195; 7,108,778; 7,110,803; and7,192,450.

Methods and devices that are suitable for use in conjunction withaspects of the preferred embodiments are disclosed in U.S. PatentPublication No. US-2005-0176136-A1; U.S. Patent Publication No.US-2005-0251083-A1; U.S. Patent Publication No. US-2005-0143635-A1; U.S.Patent Publication No. US-2005-0181012-A1; U.S. Patent Publication No.US-2005-0177036-A1; U.S. Patent Publication No. US-2005-0124873-A1; U.S.Patent Publication No. US-2005-0115832-A1; U.S. Patent Publication No.US-2005-0245799-A1; U.S. Patent Publication No. US-2005-0245795-A1; U.S.Patent Publication No. US-2005-0242479-A1; U.S. Patent Publication No.US-2005-0182451-A1; U. S. Patent Publication No. US-2005-0056552-A1;U.S. Patent Publication No. US-2005-0192557-A1; U.S. Patent PublicationNo. US-2005-0154271-A1; U.S. Patent Publication No. US-2004-0199059-A1;U.S. Patent Publication No. US-2005-0054909-A1; U.S. Patent PublicationNo. US-2005-0051427-A1; U.S. Patent Publication No. US-2003-0032874-A1;U. S. Patent Publication No. US-2005-0103625-A1; U.S. Patent PublicationNo. US-2005-0203360-A1; U.S. Patent Publication No. US-2005-0090607-A1;U.S. Patent Publication No. US-2005-0187720-A1; U.S. Patent PublicationNo. US-2005-0161346-A1; U.S. Patent Publication No. US-2006-0015020-A1;U.S. Patent Publication No. US-2005-0043598-A1; U. S. Patent PublicationNo. US-2003-0217966-A1; U.S. Patent Publication No. US-2005-0033132-A1;U.S. Patent Publication No. US-2005-0031689-A1; U.S. Patent PublicationNo. US-2004-0186362-A1; U.S. Patent Publication No. US-2005-0027463-A1;U.S. Patent Publication No. US-2005-0027181-A1; U.S. Patent PublicationNo. US-2005-0027180-A1; U. S. Patent Publication No. US-2006-0020187-A1;U.S. Patent Publication No. US-2006-0036142-A1; U.S. Patent PublicationNo. US-2006-0020192-A1; U.S. Patent Publication No. US-2006-0036143-A1;U.S. Patent Publication No. US-2006-0036140-A1; U.S. Patent PublicationNo. US-2006-0019327-A1; U.S. Patent Publication No. US-2006-0020186-A1;U. S. Patent Publication No. US-2006-0020189-A1; U.S. Patent PublicationNo. US-2006-0036139-A1; U.S. Patent Publication No. US-2006-0020191-A1;U.S. Patent Publication No. US-2006-0020188-A1; U.S. Patent PublicationNo. US-2006-0036141-A1; U. S. Patent Publication No. US-2006-0020190-A1;U.S. Patent Publication No. US-2006-0036145-A1; U. S. Patent PublicationNo. US-2006-0036144-A1; U.S. Patent Publication No. US-2006-0016700-A1;U.S. Patent Publication No. US-2006-0142651-A1; U.S. Patent PublicationNo. US-2006-0086624-A1; U.S. Patent Publication No. US-2006-0068208-A1;U.S. Patent Publication No. US-2006-0040402-A1; U.S. Patent PublicationNo. US-2006-0036142-A1; U. S. Patent Publication No. US-2006-0036141-A1;U.S. Patent Publication No. US-2006-0036143-A1; U.S. Patent PublicationNo. US-2006-0036140-A1; U.S. Patent Publication No. US-2006-0036139-A1;U.S. Patent Publication No. US-2006-0142651-A1; U.S. Patent PublicationNo. US-2006-0036145-A1; U.S. Patent Publication No. US-2006-0036144-A1;U.S. Patent Publication No. US-2006-0200022-A1; U.S. Patent PublicationNo. US-2006-0198864-A1; U.S. Patent Publication No. US-2006-0200019-A1;U.S. Patent Publication No. US-2006-0189856-A1; U.S. Patent PublicationNo. US-2006-0200020-A1; U.S. Patent Publication No. US-2006-0200970-A1;U.S. Patent Publication No. US-2006-0183984-A1; U. S. Patent PublicationNo. US-2006-0183985-A1; U.S. Patent Publication No. US-2006-0195029-A1;U.S. Patent Publication No. US-2006-0229512-A1; U.S. Patent PublicationNo. US-2006-0222566-A1; U.S. Patent Publication No. US-2007-0032706-A1;U.S. Patent Publication No. US-2007-0016381-A1; U.S. Patent PublicationNo. US-2007-0027370-A1; U. S. Patent Publication No. US-2007-0027384-A1;U.S. Patent Publication No. US-2007-0032717-A1; U.S. Patent PublicationNo. US-2007-0032718 A1; U.S. Patent Publication No. US-2007-0059196-A1;and U.S. Patent Publication No. US-2007-0066873-A1.

Methods and devices that are suitable for use in conjunction withaspects of the preferred embodiments are disclosed in U.S. applicationSer. No. 09/447,227 filed Nov. 22, 1999 and entitled “DEVICE AND METHODFOR DETERMINING ANALYTE LEVELS”; U.S. application Ser. No. 11/654,135filed Jan. 17, 2007 and entitled “POROUS MEMBRANES FOR USE WITHIMPLANTABLE DEVICES”; U.S. application Ser. No. 11/675,063 filed Feb.14, 2007 and entitled “ANALYTE SENSOR”; U.S. application Ser. No.11/543,734 filed Oct. 4, 2006 and entitled “DUAL ELECTRODE SYSTEM FOR ACONTINUOUS ANALYTE SENSOR”; U.S. application Ser. No. 11/654,140 filedJan. 17, 2007 and entitled “MEMBRANES FOR AN ANALYTE SENSOR”; U.S.application Ser. No. 11/654,327 filed Jan. 17, 2007 and entitled“MEMBRANES FOR AN ANALYTE SENSOR”; U.S. application Ser. No. 11/543,396filed Oct. 4, 2006 and entitled “ANALYTE SENSOR”; U.S. application Ser.No. 11/543,490 filed Oct. 4, 2006 and entitled “ANALYTE SENSOR”; U.S.application Ser. No. 11/543,404 filed Oct. 4, 2006 and entitled “ANALYTESENSOR”; U.S. application Ser. No. 11/681,145 filed Mar. 1, 2007 andentitled “ANALYTE SENSOR”; U.S. application Ser. No. 11/690,752 filedMar. 23, 2007 and entitled “TRANSCUTANEOUS ANALYTE SENSOR”; U.S.application Ser. No. 11/691,426 filed Mar. 26, 2007 and entitled“ANALYTE SENSOR”; U.S. application Ser. No. 11/691,432 filed Mar. 26,2007 and entitled “ANALYTE SENSOR”; U.S. application Ser. No. 11/691,424filed Mar. 26, 2007 and entitled “ANALYTE SENSOR”; U.S. application Ser.No. 11/691,466 filed Mar. 26, 2007 and entitled “ANALYTE SENSOR”; andU.S. application Ser. No. 11/692,154 filed Mar. 27, 2007 and entitled“DUAL ELECTRODE SYSTEM FOR A CONTINUOUS ANALYTE SENSOR”.

All references cited herein, including but not limited to published andunpublished applications, patents, and literature references, areincorporated herein by reference in their entirety and are hereby made apart of this specification. To the extent publications and patents orpatent applications incorporated by reference contradict the disclosurecontained in the specification, the specification is intended tosupersede and/or take precedence over any such contradictory material.

All numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification are to be understood as beingmodified in all instances by the term “about.” Accordingly, unlessindicated to the contrary, the numerical parameters set forth herein areapproximations that may vary depending upon the desired propertiessought to be obtained. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of anyclaims in any application claiming priority to the present application,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding approaches.

The above description discloses several methods and materials of thepresent invention. This invention is susceptible to modifications in themethods and materials, as well as alterations in the fabrication methodsand equipment. Such modifications will become apparent to those skilledin the art from a consideration of this disclosure or practice of theinvention disclosed herein. Consequently, it is not intended that thisinvention be limited to the specific embodiments disclosed herein, butthat it cover all modifications and alternatives coming within the truescope and spirit of the invention.

What is claimed is:
 1. An electrochemical continuous glucose sensorconfigured for implantation in a host, the glucose sensor comprising: anelectrode configured to measure a signal indicative of a glucoseconcentration of a host, wherein the signal comprises a glucose-relatedcomponent and a non-glucose related component; and a membrane coveringat least a portion of the electrode, wherein the membrane is configuredto reduce passage of an interfering species therethrough, whereby thenon-glucose-related component of the signal is less than about 20% ofthe signal over a period of at least one day; wherein the glucose sensorhas a sensitivity to glucose of from about 25 pA/mg/dL to about 500pA/mg/dL.
 2. The glucose sensor of claim 1, wherein the interferingspecies has an oxidation potential that overlaps with an oxidationpotential of a measured species indicative of the concentration of theanalyte.
 3. The glucose sensor of claim 1, wherein the measured speciesis a product of an enzymatic reaction between glucose and an enzyme andis measured by the electrode.
 4. The glucose sensor of claim 1, whereinthe membrane comprises a silicone-containing polymer.
 5. The glucosesensor of claim 4, wherein the silicone-containing polymer is apolysiloxanes.
 6. The glucose sensor of claim 4, wherein thesilicone-containing polymer is a polycarbosiloxane.
 7. The glucosesensor of claim 4 wherein the silicone-containing polymer is a copolymercomprising a silicone segment and a polyurethane segment.
 8. The glucosesensor of claim 1, wherein the membrane comprises a fluorocarbon-basedmaterial.
 9. The glucose sensor of claim 1, wherein thenon-glucose-related component is less than about 10% of the signal overa time period of at least about one day.
 10. The glucose sensor of claim1, wherein the glucose sensor has a sensitivity to glucose of from about25 pA/mg/dL to about 100 pA/mg/dL.
 11. The glucose sensor of claim 1,wherein the glucose sensor comprises an enzyme configured to react withglucose.
 12. An electrochemical continuous glucose sensor configured forimplantation in a host, the glucose sensor comprising: an electrodeconfigured to measure a signal indicative of a glucose concentration ofa host, wherein the signal comprises a glucose-related component and anon-glucose related component; and an enzyme-containing membranecovering at least a portion of the electrode, wherein theenzyme-containing membrane comprises an outer domain comprising adiscontinuously hydrophilic surface, wherein the outer domain comprisesat least about 5 wt. % of a hydrophilic component.
 13. The glucosesensor of claim 12, wherein the discontinuously hydrophilic outer domaincomprises a blend comprising a silicone-containing polymer and ahydrophilic polymer.
 14. The glucose sensor of claim 12, wherein themembrane comprises a fluorocarbon-based material.
 15. The glucose sensorof claim 12, wherein the hydrophilic polymer is a copolymer ofpoly(ethylene oxide) and poly(propylene oxide).
 16. The glucose sensorof claim 12, wherein the discontinuously hydrophilic outer domaincomprises a polyurethane-based domain that has been surface-treated witha polymer containing hydrophilic moieties
 17. The glucose sensor ofclaim 12, wherein the outer domain comprises at least about 15 wt. % ofa hydrophilic component.
 18. The glucose sensor of claim 12, wherein theouter domain comprises at least about 25 wt. % of a hydrophiliccomponent.
 19. The glucose sensor of claim 12, wherein the glucosesensor has a sensitivity to glucose of from about 25 pA/mg/dL to about500 pA/mg/dL.
 20. The glucose sensor of claim 12, wherein the glucosesensor has a sensitivity to glucose of from about 25 pA/mg/dL to about100 pA/mg/dL.